Background. The prognosis of patients with squamous cell cancer of the anus is most dependent on tumor staging and histopathology. Recent evidence suggests that the adaptive immune response, represented by T cells, is important in predicting clinical outcome in colon and other cancers. CD8+ T cells are a subpopulation of cytotoxic immune cells that have the potential to respond to and kill cancer cells. In this study, we correlated CD8+ T cell tumor infiltration with histopathology, HIV and HPV status, and anal cancer recurrence. Methods. Archived, formalin-fixed tissues from 16 cases of squamous cell cancer of the anus were analyzed for CD8+ T cell infiltration using an anti-CD8 antibody. High-power microscope images were taken of the tumor with CD8+ cells counted by two observers. Tumors were called high infiltration if >150 CD8+ cells/HPF, low infiltration if <10 CD8+cells/HPF, and medium infiltration if >10 and <150 CD8+ cells/HPF. Each case was reviewed for histopathologic grade of tumor (well, moderate or poorly differentiated). This data was then correlated with retrospective clinical data on HIV status, and cancer recurrence after IRB approval was obtained. Results. Of the sixteen cases of anal cancer included in the study, the histopathology showed: well-differentiated 4/16 (25%), moderately-differentiated 7/16 (44%) and poorly-differentiated 5/16 (31%). HIV was documented in 7/16 (44%) of cases. The overall recurrence rate in this population was 6/16 (37%). High CD8+ T cell infiltration was seen in 6/16 (37%) of cases, medium 4/16 (31%), and low infiltration in 6/16 (38%) of cases. There was a significant correlation between high CD8+ T cell infiltration and well to moderately differentiated tumors and between low CD8+ T cell infiltration and poorly differentiated tumors (p<0.05). Of the patients with cancer recurrence two-thirds had low CD8+ T cell infiltration (p<0.05). Of the seven patients in our cohort that were HIV positive, 70% of these patients had low CD8+ T cell infiltration (p<0.05).Conclusions. There is a strong correlation of infiltrating CD8+ T cells with anal cancer tumors and histopathologic diagnosis, HIV status and cancer recurrence. The CD8+ T cell infiltration may confer part of the improved survival observed in HIV negative patients and in those patients with tumors that are well to moderately differentiated.