Background: Cardiovascular disease (CVD) causes significant morbidity and mortality in HIV-infected individuals. Advancing age, chronic HIV-associated inflammation and antiretroviral therapy in part contributes to the increased risk of CVD in these patients. Aim: This study aimed to compare the CVD- and HIV-related morbidity of subjects prior to initiating an non-nucleoside reverse transcriptase inhibitor (NNRTI)- versus a protease inhibitor (PI)-based HAART regimen. Methods: Subjects in this retrospective, observational study of medical claims data representing HIV-infected beneficiaries from May 2000 to December 2009 were assigned either to a PI initiator group (n = 2192) or to a NNRTI initiator group (n = 3338). The case mix similarities and differences between the two groups were compared. Results: More subjects in the PI group had previous treatment with nucleoside reverse transcriptase inhibitor therapy or with the fusion inhibitor enfuvirtide, whereas more subjects in the NNRTI group had prior treatment with lamivudine plus zidovudine. Uncontrolled Type 2 diabetes, substance abuse, drug dependence, cardiovascular morbidity, heart failure, nonhypertension kidney dysfunction, depression, AIDS-related diagnosis, Kaposi‘s sarcoma, candidiasis and cachexia were observed more often in the PI group. Subjects in the PI group were more likely to be receiving medications for AIDS conditions. Only smoking cessation medication showed a higher prevalence in the NNRTI group. Conclusion: Subjects initiating PI-based versus NNRTI-based therapy had a greater prevalence of specific comorbidities that may adversely affect CVD risk profile.