SEMA3B has been implicated as important for neuronal development and as a tumor suppressor in lung cancer. A single nucleotide alteration of this gene leads to the amino acid substitution T415I, and functionally, this variant protein has a reduced ability to act as a tumor suppressor. The prevalence of this variant in populations is unclear and its role in inherited lung cancer susceptibility has not been tested. Utilizing case-control studies of head and neck squamous cell carcinoma in a Caucasian population and of lung cancer in African-American and Latino-American populations, we determined both the prevalence of this polymorphic variant and its association with the case status of these patients. The variant Ile allele occurs at an allele frequency of 0.18 in African-American and 0.39 in Latino-American control subjects but not in Caucasian subjects. In analyses controlling for ethnicity and known lung cancer risk factors, a significant association was observed between case status and possession of the variant allele (OR 0.71, 95% CI 0.51-0.99). In stratified analysis, both Latino-Americans (OR 0.56, 95% CI 0.32-1.01) and African-Americans (OR 0.75, 95% CI 0.50-1.13) also showed a reduced risk of disease associated with the variant Ile allele. Possessing either the heterozygous or homozygous variant genotype confers a >40% reduced relative risk of lung cancer in Latino Americans controlling for other lung cancer risk factors. This study points to the need for further examination of this gene and its variant in lung cancer and other diseases.