Objective To compare the efficacy of single dose antimicrobial prophylaxis with multiple doses for caesarean section at Federal Teaching Hospital Gombe. Design Parallel arm randomized controlled trial (1:1 allocation) comparing single and multiple dose antimicrobial prophylaxis for caesarean section. Setting Federal Teaching Hospital Gombe, Nigeria. Population 176 women undergoing elective and emergency caesarean sections. Methods Participants were randomized into two groups: single dose of intravenous Amoxicillin/Clavulanic acid before skin incision only (Group A) and multiple doses including postoperative doses (Group B). Main Outcome Measures Surgical site infection rate during a 30-day surveillance period. Results The surgical site infection rate was 2.3% in Group A and 0.0% in Group B (p = 0.058). Febrile morbidity was 1.2% and 2.3% respectively (p = 0.509). Urinary tract infection occurred in one patient in Group A (p = 0.494). Conclusions Single dose antimicrobial prophylaxis for caesarean section is as effective as multiple doses in preventing surgical site infection. This trial was registered in the Pan African Clinical Trial Registry ([www.pactr.org](http://www.pactr.org) ) database with unique identification number PACTR202009483150226.