Introduction: Cesarean section (CS) rates are increasing globally with an unclear effect on pregnancy outcomes. The study objective was to quantify maternal and perinatal morbidity and mortality associated with CS compared with vaginal delivery (VD) both within and across sites in low- and middle-income countries. Material and methods: A prospective population-based study including home and facility births in 337 153 women with a VD and 47 308 women with a CS from 2010 to 2015 was performed in Guatemala, India, Kenya, Pakistan, Zambia and Democratic Republic of Congo. Women were enrolled during pregnancy; delivery and 6-week follow-up data were collected. Results: Across all sites, CS rates increased from 8.6% to 15.2%, but remained low in African sites. Younger, nulliparous women were more likely to have a CS, as were women with higher education and those delivering an infant weighing 1500–2499 g. Across all sites, maternal and neonatal mortality was higher, and stillbirths were lower, in pregnancies delivered by CS. Antepartum and postpartum complications as well as obstetric interventions and treatments were more common among women who underwent CS. In stratified analyses, all outcomes were worse in women with a CS compared with VD in African compared to non-African sites. Conclusions: CS rates increased across all sites during the study period, but at more pronounced rates in the non-African sites. CS was associated with reduced postpartum hemorrhage and lower rates of stillbirths in the non-African sites. In the African sites, CS was associated with an increase in all adverse outcomes. Further studies are necessary to better understand the increase in adverse outcomes with CS in the African sites.