Background: Genetic influences on self-medication with over-the-counter (OTC) drugs merit investigation. For example, patients frequently use OTC nonsteroidal anti-inflammatory drugs (NSAIDs) to treat inflammation, but the inflammatory response is also affected by endogenous cytokines whose production varies across polymorphisms of their encoding genes. In the case of interleukin 10 (IL-10), literature suggests that a single nucleotide polymorphism (SNP) in the promoter region of the cytokine's gene (-1082 A >G [rs1800896]) influences production with higher levels associated with G variant alleles. Objective: To demonstrate the feasibility of researching the role of genetics in self-medication by using existing national survey data to evaluate a possible association between OTC NSAID use and genotype at the -1082 SNP of the IL-10 gene. Methods: Statistical analyses were performed using data from 6,309 participants in the Third National Health and Nutrition Examination Survey (NHANES III). Results: OTC NSAID use (aspirin or ibuprofen) in the previous month was significantly more common among persons with AG or GG genotypes at the -1082 SNP. Odds of use consistently increased relative to the number of G alleles. This trend remained statistically significant (odds ratio = 1.14 per additional G allele, p = .02, 95% confidence interval [1.02, 1.27]) after adjustment for confounding. Conclusions: Analysis of population-based genetic data suggests an association between a common self-medication behavior and a specific genetic polymorphism. These findings broadly demonstrate that NHANES data provide opportunities to investigate such associations and specifically imply that potential interrelationships among OTC NSAID use, IL-10 genotype, and IL-10 cytokine levels deserve further study.