OBJECTIVE: To determine if extended spectrum prophylactic antibiotic treatment (with efficacy against Ureaplasma urealyticum) reduces post-cesarean delivery clinical endometritis. METHODS: After cord clamping at cesarean delivery, subjects received prophylaxis with cefotetan. Subjects were then simultaneously randomized (double blind) to receive doxycyline plus azithromycin versus placebo. Post-cesarean delivery endometritis was defined clinically as fever of 100.4F or higher with one or more supporting clinical signs or a physician diagnosis of endometritis plus the absence of a nonpelvic source of fever. RESULTS: A total of 597 women were enrolled, 301 in the doxycycline/azithromycin group and 296 in the placebo group. The study population was 56% black, 25.5 ± 6.2 years of age, and 43% nulliparous. The groups were similar (P > .05) for black race, parity, maternal age, and most risk factors for post-cesarean delivery endometritis. The frequency of post-cesarean delivery endometritis (16.9% versus 24.7%, P = .020), wound infections (0.8% versus 3.6%, P = .030), and a combination of these two outcomes (19.0% versus 27.8%, P = .019) were significantly lower in the doxycycline/azithromycin group compared with the placebo-treated group. The doxycycline/azithromycin versus placebo groups were dissimilar for maternal leukocytosis (24.9% versus 12.5%, P = .042) and frequency of classic uterine incision (7.6% versus 12.5%, P = .048). Adjusting for these factors did not alter the risk ratio for post-cesarean delivery endometritis in the active versus placebo-treated group (relative risk 0.65, 95% confidence interval 0.43, 0.98). Length of stay was longer in the placebo group overall (104 ± 56 versus 95 ± 32 hours, P = .016) and among women with endometritis (146 ± 52 versus 127 ± 46 hours, P = .047). CONCLUSION: Extended spectrum prophylactic antibiotic treatment (with presumed efficacy against U urealyticum) given to women undergoing cesarean delivery at term shortens hospital stay and reduces the frequency of post-cesarean delivery endometritis and wound infections. © 2003 by The American College of Obstetricians and Gynecologists.