Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common human malformations with an average prevalence of 1 in 1,000 live births. The cause(s) of NSCLP remain unclear as the relative roles of genes, of the environment, and/or of chance alone are unknown. The purpose of this study was to evaluate the potential role of environmental factors in the cause of NSCLP, to determine if other birth defects aggregate in families with at least one individual affected with NSCLP, and to investigate the frequency of cancer in the first-and second-degree relatives of NSCLP index-cases. Included in this study were 196 index-cases and their families. Information pertaining to environmental factors and pedigree information was obtained on each family. Analysis showed that no single environmental factor could explain the occurrence of NSCLP in this population. The frequency of other birth defects in these families was 1.2%, which is not increased over that in the general population. One hundred seven cancers were reported in 72 of the 196 families included in the study. The frequency of cancer was not significantly increased in the first-or second-degree relatives of the NSCLP index cases or in those families with a positive family history of NSCLP. No childhood or adult cancers were reported in any of the 196 NSCLP index cases.