Matteo Berrettini defeated John Millman 6–4, 6–2 in the first round of the Rome Masters on clay on 12 May 2021, a result that confirmed pre-match expectations as Berrettini was the heavy favourite at 1.15 odds. The Italian controlled proceedings from the outset, breaking Millman's serve multiple times and maintaining consistent pressure throughout both sets. Millman, competing at 6.34 odds, struggled to find rhythm on the red clay and could not generate sufficient break opportunities to threaten Berrettini's serve. The dominant performance underlined Berrettini's status as a top clay-court player and positioned him favourably for the tournament's latter stages.