Abstract African Americans are more likely to develop lung cancer and die from it than any other ethnic group. Complex biological, environmental, political and cultural factors contribute to this disparity. The purpose of the current project is to examine the relationship between epigenetic factors, gender, ethnicity and outcome in a retrospective study of patients with surgically-treated early stage lung cancer. Fixed primary tumor tissues from a private (RMC) and a public (JHS-CCH) institution were analyzed in this study. The RMC group consisted of 132 patients with stage Ib, IIa and IIb NSCLC, 22% African-American (AA) and 52% female. The JHS-CCH group consisted of 88 patients, 62% AA and 43% female. Five year survival was achieved by 85% of women vs 67% of men in the RMC group (Chi square p=0.022). 68% of Caucasians vs 53% AA survived five years in the RMC group (p=0.186). To investigate the role of epigenetic influences on survival, promoter methylation of Ras association domain family protein 1, RASSF1A, was investigated. Associations between inactivation of the RASSF1A tumor suppressor and poor outcome in lung and other cancers have been reported in several studies. Promoter methylation was quantified using pyrosequencing. Percent methylation of RASSF1 at cytosine position –36 (A of ATG=+1) was more frequent in AA (41% of cases) than in Caucasians (20% of cases) in the RMC group (p=0.023) compared to 69% of cases in the JHS-CCH group. Methylation levels of RASSF1 at all CpG sites tested were higher in the JHS-CCH group than in the RMC group. Kaplan-Meier analysis was performed on dichotomized hypermethylation status compared to five-year survival (5YS). Promoter hypermethylation of RASSF1 was significantly associated with shortened 5YS in AA (p=0.005), compared to Caucasians (p=0.197) in the RMC group. Although 5YS was marginally shortened with hypermethylation of RASSF1 in men in the RMC group (p=0.123), no significant effects were seen with regard to gender. These results suggest that biomarkers can have differential effects, based on genetic background and support analysis of epigenetic biomarkers to address disparities and develop more personalized treatment strategies for individual patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3586. doi:1538-7445.AM2012-3586