Because obstructive sleep apnea (OSA) is associated with increased levels of inflammatory cytokines, we examined the relationship between OSA and polymorphisms for interleukin‐6 (IL6). Six single nucleotide polymorphisms (SNPs) within IL6 were genotyped in 259 African Americans from the Cleveland Family Study with replication conducted in the Cardiovascular Health Study (n= 124). OSA was dichotomized into apnea hypopnea index (AHI) > 15, or on treatment versus absent: AHI < 5. Logistic regression was conducted, adjusting for age and sex in models with and without body mass index (BMI). SNP IL6–6021 was associated with a decreased risk of OSA after adjusting for BMI (Odds Ratio for T allele 0.24, 95%CI [0.09–0.67], p= 0.006, q= 0.07) under an additive model. This same allele was associated with increased BMI. The results from the replication sample were consistent in direction though not statistically significant (p= 0.23). The SNPs were studied in European‐ Americans, although, the minor allele frequency in IL6–6021 was too low (4%) for meaningful comparisons. A synonymous SNP within the IL6 coding region was protective of OSA in African Americans; with qualitatively similar findings observed in another cohort. This suggests that variants in IL6 may influence the risk of OSA in a pathway that is not explained by obesity. Clin Trans Sci 2010; Volume 3: 337–339