Previous studies suggest that the risk of nonsyndromic cleft lip with or without cleft palate (CL+/-P) and isolated cleft palate (CP) is influenced by genetic variation at several loci and that the relation between specific genetic variants and disease risk may be modified by environmental factors. The present study evaluated potential associations between CL+/-P and CP and two putative clefting susceptibility loci, MSX1 and TGFB3, using data from a nationwide case-control study conducted in Denmark from 1991 to 1994. The potential effects of interactions between these genes and two common environmental exposures, first trimester exposure to maternal cigarette smoke and alcohol intake, were also examined. Analyses of these data provide evidence of an association between the risk of CP and variation at the TGFB3 locus. However, there is no evidence that the risk of CL+/-P or CP is influenced by gene-environment interactions involving MSX1 or TGFB3 and either first trimester exposure to maternal cigarette smoke or alcohol consumption.