Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial malformation in humans. Three polymorphisms, rs2235371 and rs642961 in interferon regulatory factor 6 (IRF6), rs987525 on 8q24, have been shown to be associated with NSCL/P risk in several studies. However, the magnitudes of the association varied between studies. We therefore performed a meta-analysis to investigate this relationship. Two authors independently extracted information on the characteristics of the eligible studies. Either a fixed- or a random-effects model was used to calculate the overall combined risk estimates. Overall, 20 published case–control studies were included in the meta-analysis. We found that rs2235371 A allele had a significantly decreased risk (OR: 0.73, 95% CI: 0.61–0.88), whereas rs642961 A allele had a significantly increased risk of NSCL/P (OR: 1.44, 95% CI: 1.30–1.59), compared with the G allele. For 8q24 rs987525, the A allele was associated with a significantly increased risk of NSCL/P, compared with the C allele (OR: 1.71, 95% CI: 1.40–2.09). Furthermore, in the stratified analysis by ethnicity and types of NSCL/P, significant associations were still observed in the subgroups of ethnicity and types. Taken together, the results suggest that the IRF6 rs2235371, rs642961, and 8q24 rs987525 polymorphisms are associated with NSCL/P risk. © 2012 Wiley Periodicals, Inc.