Objectives: To determine the effectiveness of a single perioperative prophylactic 2 g dose of cephalexin in preventing surgical site infection (SSI) following excision of skin lesions from the lower limb. Design: Prospective double-blinded placebo-controlled trial testing for difference in infection rates. Setting: Primary care in regional North Queensland, Australia. Participants: 52 patients undergoing lower limb skin lesion excision. Interventions: 2 g dose of cephalexin 30–60 min before excision. Main outcome measures: Incidence of SSI. Results: Incidence of SSI was 12.5% (95% CI 2.7% to 32.4%) in the cephalexin group compared with 35.7% (95% CI 18.6% to 55.9%) in the placebo group (p=0.064). This represented an absolute reduction of 23.21% (95% CI −0.39% to 46.82%), relative reduction of 65.00% (95% CI −12.70% to 89.13%) and number-needed-to-treat of 4.3. Conclusions: Administration of a single 2 g dose of cephalexin 30–60 min before skin lesion excision from the lower limb may produce a reduction in the incidence of infection; however, this study was underpowered to statistically determine this. Trial registration number: ACTRN12611000595910.