OBJECTIVE Despite improvements in cancer treatment, the prognosis of ovarian cancer remains low and imperfectly predicted by traditional pathologic criteria. Biomarkers that predict prognosis independently of such criteria shed light on important molecular variations, aiding in the development and targeting of novel therapies. Previous work has shown human leukocyte antigen (HLA) class I antigen expression to be independently predictive of prognosis in colorectal and breast cancer. We investigated the prognostic potential of HLA class I antigen expression by studying a large series of ovarian cancers. METHODS A tissue microarray of 339 ovarian cancer cases linked to prospectively recorded clinicopathologic and follow-up data was constructed. This was stained following a standard immunohistochemical protocol for HLA class I heavy chain (HC-10) and beta(2)-microglobulin (beta(2)-m). HLA class I antigen expression was compared with clinicopathologic factors and overall disease-specific survival using the Pearson chi(2) test, Kaplan-Meier curves, and the log-rank test. Cox regression was used to test for the independence and magnitude of effects. RESULTS There were no univariate correlations between HLA class I antigen expression and clinicopathologic factors. Deviation from an HC-10(+)/beta(2)-m(+) phenotype correlated with reduced survival in univariate analysis (log-rank, 5.69; P = 0.017); a retained HC-10(+)/beta(2)-m(+) phenotype predicted improved prognosis independently of age, stage, level of cytoreduction, and chemotherapy usage on multivariate analysis (hazard ratio, 0.587; 95% confidence interval, 0.442-0.781; P < 0.001). CONCLUSIONS HLA class I antigen expression is an independent prognostic marker in ovarian cancer, its loss correlating with a poor prognostic outcome.