BACKGROUND This trial aimed to compare the influence of administering a single dose or 24h of prophylactic antibiotics on surgical site infection (SSI) rates after reduction mammaplasty. METHODS This is a randomized, non-inferiority, parallel-arm clinical trial with a 1:1 allocation ratio. One hundred forty-six participants undergoing reduction mammaplasty were randomly assigned to the placebo group (PG), which received cefazolin 1g at the time of anesthesia induction (n=73), or to the antibiotic group (AG), which received cefazolin 1g at the time of anesthesia induction and every 6h for 24h (n=73). No antibiotics were prescribed to any of the participants after this period. SSI occurrence was evaluated using criteria and definitions from the Centers for Disease Control and Prevention. The participants were assessed weekly for 30 days by a surgeon blinded to group allocation. RESULTS There were no significant differences between the groups in terms of main characteristics. The median age, body mass index, weight of excised breast tissue, and surgery time of the 146 participants were 33 years, 25.2 Kg/m², 925 g, and 220 min, respectively. Superficial dehiscence occurred in 30 patients (20.5%), with 16 in the placebo group and 14 in the antibiotic group (P=0.682). Eight participants (5.5%) had SSI, with four in each group (P=1.000). In all cases, SSI was classified as superficial incisional. CONCLUSIONS Our results suggest that extending antibiotic prophylaxis beyond a single dose administered during anesthesia induction does not significantly reduce the incidence of SSIs or wound dehiscence in reduction mammaplasty. BACKGROUND Clinicaltrials.gov. NCT04079686.