Edin Dzeko, just as he did two years ago in the Europa League against the same opponent, scored a hat-trick to take the game away from the Czech champions - as Cengiz Under and Justin Kluivert also got on the scoresheet.
Kluivert, at 19 and 150 days, became the youngest Roma goalscorer in the competition when he tapped home late in the second half.
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It was Dzeko, however, who got the Giallorossi off to the perfect start - beating the offside trap after three minutes to break the deadlock.
A second followed shortly before half-time, as he controlled Cengiz Under's inswinging cross before half-volleying home emphatically.
That gave the Giallorossi the freedom they needed, and some enjoyable football emerged in the second half. One such passing move was completed by Cengiz, as he latched onto Lorenzo Pellegrini's pass to curl home expertly.
When Kluivert followed suit - cleaning up after Cengiz's cross-shot had been parried into his path - the Stadio Olimpico was really enjoying itself.
And then, to cap it all off, Dzeko completed his hat-trick with a header in the very last action of the game.
Roma are next in Champions League action against CSKA Moscow in three weeks' time.
Alessandro Florenzi captained Roma, as Cengiz Under and Justin Kluivert started in the same team for the first time.
Coach Eusebio Di Francesco opted for youth alongside Edin Dzeko in attack, while Steven Nzonzi, Lorenzo Pellegrini and Bryan Cristante occupied the midfield.
Juan Jesus was drafted into the defence, replacing Kostas Manolas.
3' - GOAL! Dzeko just loves playing against Plzen! The striker beats a misjudged attempt at an offside trap, dribbles into the box and fires home from an acute angle! Get in! 1-0!
13' - Chance for Krmencik, but he can't turn his shot on target from just outside the six-yard box. Escape for the hosts.
16' - Good spell for Roma. Dzeko forces a save from Kozacik and, moments later, Kluivert nearly gets on the end of Cengiz's dangerous low cross.
20' - Free header inside the box for Reznik, but he plants his attempt wide with Olsen watching on anxiously.
29' - BAR! So close for Cengiz, who cuts inside from the right in trademark fashion and hits a rasping, curling effort that cannons away off the frame of the goal!
36' - Dzeko rises highest to plant his header on target, but it is comfortable for Kozacik.
40' - GOAL! Emphatic stuff again from Dzeko, as he chests down Cengiz's inswinging cross, before lashing a powerful shot from close range that gave Kozacik no chance! 2-0!
44' - Chance for Florenzi inside the box, but Kozacik makes a great stop!
52' - Good headed chance for Cengiz Under at the back post, but he can't keep his attempt down under some late pressure from the defender.
64' - GOAL! Beautiful team move from the Gialloross! Kolarov plays it into Dzeko who flicks it on brilliantly for Pellegrini - the midfielder then slots the ball behind the defence for Cengiz, who finishes expertly! 3-0!
70' - Good work from Kluivert gives Dzeko a clear sight of goal in pursuit of his hat-trick, but Kozacik somehow makes the save.
73' - GOAL! KLUIVERT! A straightforward finish for the Dutchman, as he cleans up after Cengiz Under's shot is parried out awkwardly by Kozacik! 4-0!
90' - GOAL! DZEKO HAT-TRICK! The striker heads home, and the match ball goes back with him! 5-0!
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“I played in the Czech Republic, even with Teplice I scored a few goals against them. Today is my first Champions League hat-trick and I have to be happy with that.”
- Edin Dzeko
“I was trying to find the right solutions for this team. We all know it’s never easy to experiment at Roma, but I’ve always tried to put the players in the right system. I didn’t want to change my 4-3-3 completely, but eventually I realised it was necessary to change something with the players and the set-up. We’ve come up with the correct response, so now I’ll try to change things as little as possible."
- Eusebio Di Francesco
The Giallorossi have one more game before the international break - they travel to face Empoli in the late kick-off on Saturday.
There next Champions League engagement is against CSKA Moscow, at the Stadio Olimpico once again, at the end of the month.
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