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Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies.We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 patients with HIV-related diffuse large B-cell lymphoma (DLBCL) diagnosed in the era of combined antiretroviral therapy (1996–2007) at Kaiser Permanente California. Eighty patients with HIV-unrelated DLBCL were included for comparison.Data on patients’ clinical history were obtained from Kaiser Permanente's electronic health records. The density of stromal CD4+, CD8+ and FOXP3+ T cells and CD68+ macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient's clinical history or tumor characteristics were examined using Kruskal–Wallis tests or Pearson's correlation coefficient. The effect of stromal immune infiltration on 2-year mortality was evaluated in multivariable logistic regression.Compared with HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4+ and FOXP3+ T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4+ cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not Epstein–Barr virus infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3+ T cells. A higher density of infiltrating CD8+ T cell was significantly associated with reduced mortality in patients with HIV-related DLBCL (odds ratio = 0.30 [0.09–0.97] for ≥25 vs. <10%).These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.