A high proportion of peripartum maternal deaths are caused by infection and sepsis, and this proportion continues to rise. In addition, neonatal sepsis is the third most common cause of neonatal death; the 2 conditions are connected in that maternal infection causes an increased risk of neonatal sepsis. Recent studies have shown azithromycin to be effective in reducing instances of maternal infection after an unplanned cesarean delivery, but its effectiveness for infections related to vaginal delivery has not yet been examined. This study, A-PLUS (Azithromycin Prevention in Labor Use Study), was designed to investigate the effectiveness of azithromycin in women planning a vaginal delivery. This study was conducted as a multicountry, double-blind, placebo-controlled, randomized trial over 8 sites in 7 countries. Primary outcomes included maternal sepsis or death within 6 weeks of delivery, as well as stillbirth, neonatal death, or sepsis within 4 weeks of delivery. Secondary maternal outcomes included related components, such as specific infections of chorioamnionitis, endometritis, perineal wound infection, abdominal or pelvic abscess, mastitis or breast abscess, pneumonia, or pyelonephritis, as well as therapeutic use of antibiotics, duration of hospital stay, readmission, admission to a special care unit, and unscheduled health care visits. Secondary outcomes relating to neonates included similar components, specific infection, the duration of hospital stay, readmission, admission to a special care unit, unscheduled health care visits, and safety outcomes (adverse events related to medication). Final analysis included 29,278 women, with 14,590 women (and 14,687 neonates or stillbirths) in the azithromycin group and 14,688 women (and 14,782 neonates or stillbirths) in the placebo group. Maternal sepsis or death was observed in 227 patients in the azithromycin group and 344 patients in the placebo group (adjusted relative risk, 0.67; 95% confidence interval [CI], 0.56-0.79; P < 0.001). Sepsis was the case in 219 in the azithromycin group and 339 in the placebo group (relative risk, 0.65; 95% CI, 0.55-0.77), and death from sepsis was rare. For neonates, stillbirth, death, or sepsis was observed in 1540 in the azithromycin group and 1526 in the placebo group (relative risk, 1.02; 95% CI, 0.95-1.09), with sepsis accounting for 1433 and 1407 cases in the azithromycin and placebo groups, respectively. Both the outcomes of stillbirth and neonatal death were relatively uncommon. Maternal adverse effects experienced from the medication were not significantly different between groups, and the azithromycin group had noticeably reduced risk of endometritis, wound infections, and several others when compared with the placebo group. These results indicate that azithromycin is consistently effective in lowering the risk of infection and sepsis in mothers and infants during vaginal delivery. The number treated to prevent 1 case of maternal death or sepsis was 125; this is consistent with previous research in individuals undergoing cesarean delivery. Although azithromycin was effective at preventing maternal infection and sepsis, there were no significant effects on neonatal outcomes. This is consistent with most previous research; reasons for discrepancies could be inclusion of different types of infections and differences in antibiotic treatment between countries. Further research could improve the generalizability of these findings by focusing on factors that influence the effectiveness of azithromycin and that impact its clinical use.