Argyle, who slumped to their first home defeat since Tony Pulis was appointed manager in September, were never in a position to repeat their 2-1 opening-day win at the Madejski.
Glenn Little, in the first half, and Kevin Doyle, in the second, scored the goals that made sure of a new Reading club record run of 23 games in all competitions without defeat.
Pulis handed full debuts to loan signings Elliott Ward, from West Ham, and Norwich's Jason Jarrett against unchanged Reading, who included six players in their starting 11 who had started all the Royals' previous 20 matches this season.
The game arguably turned on 30 topsy-turvy seconds midway through the first half.
Reading's American international goalkeeper Marcus Hahnemann made a superb save after Plymouth's former Everton striker Nick Chadwick had skipped through the Reading defence, sprinting from his line quickly to block.
Within three passes, Little found himself on the edge of the Argyle area and, spotting Plymouth's French goalkeeper Romain Larrieu off his line, beat him with an exquisite chip.
Larrieu saved well from Ivar Ingimarsson's snap-shot after Steve Sidwell had beaten the offside trap to keep Argyle in the match, before David Norris came close to a leveller when he blasted just wide of the post at the beginning of the second half.
Immediately, Reading stole down to the other end and sealed the match, Bobby Convey linking with Leroy Lita before Irishman Kevin Doyle touched home from a yard.
Chadwick headed a cross from Argyle substitute Bojan Djordjic past Hahnemann, but was unlucky enough to see the effort crash back off the crossbar.