OBJECTIVE: Our purpose was to determine whether chlorhexidine vaginal irrigation prevents maternal peripartal infection. STUDY DESIGN: A double- blinded, placebo-controlled, randomized trial was performed. Single 200 ml irrigations of either 0.2% chlorhexidine solution or sterile water placebo were given in active labor or before planned cesarean delivery. The primary outcome measure was the combined rate of chorioamnionitis and endometritis (which were mutually exclusive diagnoses). RESULTS: A total of 1024 patients were enrolled: 508 in the chlorhexidine group and 516 in the placebo group. The two groups were generally well balanced on important clinical factors but differed (p < 0.05) in rates of nulliparity (chlorhexidine 42%, placebo 52%), intrauterine pressure catheter usage (chlorhexidine 65%, placebo 72%), and presence of meconium (chlorhexidine 17%, placebo 22%). There were no recognized adverse maternal or neonatal reactions to irrigation. Rates of infection (chorioamnionitis + endometritis) did not differ significantly between the groups, chlorhexidine 10% versus placebo 13% (relative risk 0.8, 95% confidence interval 0.5 to 1.1). Stratified and logistic regression analyses supported the primary univariate analysis. Neonatal outcomes, including sepsis rates of 0.4%, were equivalent for the groups. CONCLUSION: As used in this trial, chlorhexidine lacked efficacy in the prevention of maternal peripartal infection.