BACKGROUND: Orofacial clefts (OFC) are linked with several genetic and environmental factors. The aim of this study was to explore the association of potential risk factors with OFCs in India. METHODS: This was a hospital-based, matched case-control (1:4 ratio; matching done for parity) study conducted in Hyderabad, Bengaluru, and Delhi-National Capital Region. Cases (nonsyndromic clefts) were recruited from treatment centers, while controls (live births) were recruited from maternity centers. Information on exposures was collected during personal interviews. Exposures of interest included folic acid supplementation during the peri-conceptional period, consanguineous marriage, exposure to drugs, infections during pregnancy, family history of OFC, and dietary factors. RESULTS: A total of 785 participants were included in the study: 157 cases and 628 controls. A family history of cleft lip/palate (adjusted odds ratio [AOR], 15.48; 95% confidence interval [CI], 4.36-54.96; p value = 0.001), exclusive vegetarianism (AOR, 4.47; 95% CI, 1.83-10.98; p value = 0.001), and delayed first conception (AOR, 2.55, 95% CI, 1.25-5.21, p = 0.01) were found to be strongly associated with higher risk of OFCs. Supplementation with folic acid during first 3 months of pregnancy was not found to be protective against OFCs (AOR, 1.24; 95% CI, 0.59-2.58; p value = 0.56). CONCLUSION: Our study confirmed the importance of family history as a risk factor for OFC. Our study did not show an association with folic acid supplementation but was underpowered to detect small effects. Our finding of higher risk among vegetarians requires replication. Birth Defects Research 109:1284-1291, 2017. © 2017 The Authors. Birth Defects Research Published by Wiley Periodicals, Inc.