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Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with a better prognosis in high-grade serous ovarian cancer (HGSC). However, it is largely unknown how this prognostic benefit of TIL relates to current standard treatment of surgical resection and (neo-)adjuvant chemotherapy. To address this outstanding issue, we compared TIL infiltration in a unique cohort of patients with advanced-stage HGSC primarily treated with either surgery or neoadjuvant chemotherapy.Experimental Design: Tissue microarray slides containing samples of 171 patients were analyzed for CD8 þ TIL by IHC.Freshly isolated CD8 þ TIL subsets were characterized by flow cytometry based on differentiation, activation, and exhaustion markers. Relevant T-cell subsets (CD27 þ ) were validated using IHC and immunofluorescence.Results: A prognostic benefit for patients with high intratumoral CD8þ TIL was observed if primary surgery had resulted in a complete cytoreduction (no residual tissue). By contrast, optimal (<1 cm of residual tumor) or incomplete cytoreduction fully abrogated the prognostic effect of CD8 þ TIL. Subsequent analysis of primary TIL by flow cytometry and immunofluorescence identified CD27 as a key marker for a less-differentiated, yet antigen-experienced and potentially tumor-reactive CD8 þ TIL subset. In line with this, CD27 þ TIL were associated with an improved prognosis even in incompletely cytoreduced patients. Neither CD8 þ nor CD27 þ cell infiltration was of prognostic benefit in patients treated with neoadjuvant chemotherapy. Conclusions: Our findings indicate that treatment regimen, surgical result, and the differentiation of TIL should all be taken into account when studying immune factors in HGSC or, by extension, selecting patients for immunotherapy trials. Clin Cancer Res; 22(3); 714-24. Ó2015 AACR.