Abstract: Background: The study describes the cancer trends in a Puerto Rican Hispanic HIV/AIDS cohort for three different time periods as defined by the availability of combination antiretroviral therapy (cART) in the Island: Pre (1992-1995), early (1996-2002) and recent (2003-2009). Methodology: AIDS and non-AIDS related malignancies risk, standardized incidence rate and 1 year mortality were evaluated in the cohort before and after cART. Results: Of the 281 malignancies found in 265 persons; 72% in men, 38% in injecting drug users and 42.3% in AIDS related cancers. The AIDS related cancer standardized incidence rates decreased significantly in the cART eras; however, Kaposi’s sarcoma and invasive cervical carcinoma incidence remained significantly higher in the cohort when compare to the general population. On the contrary, non-AIDS related cancer standardized incidence rates increased significantly in the cART eras, specifically those of the oral/cavity/pharynx, liver, anus, vaginal and Hodgkin’s and non-Hodgkin’s Lymphomas. Around 50% of the persons with cancers were reported dead within the 1st year of their diagnoses without a significant variation during the cART eras. Conclusion: The higher incidence of Kaposi’s sarcoma, invasive cervical carcinoma, non-AIDS related malignancies and their high mortality in the cART eras is suggestive of the role of oncogenic viruses, environmental agents, risky lifestyle behaviors and inadequate cancer prevention efforts that contribute and accelerate the risk of malignant transformation in these subjects. Aggressive intervention in the form of vaccines, risky practice reduction, early screening, early treatment and adequate risk reduction education needs to be incremented in this vulnerable population.