The high prevalence of comorbidity among HIV-infected patients in care such as hepatitis C virus (HCV) coinfection and mental illness may contribute to increased toxicity and decreased adherence to highly active antiretroviral therapy (HAART). Newer HAART regimens have less toxicity and better dosing characteristics than first-generation regimens, but it is not known whether they are associated with improved clinical outcomes. The purpose of this study was to examine the effect of patient factors and initial HAART regimen on survival among HIV-infected patients in routine care. We conducted an observational study of all HAART-naïve patients in the University of Washington HIV cohort who initiated HAART between January 1996 and October 2005. Cox survival analyses were used to examine the association between time to death and treatment with first-generation protease inhibitors (PIs; indinavir, ritonavir, saquinavir), newer PIs (amprenavir, atazanavir, lopinavir, nelfinavir), efavirenz, or nevirapine, controlling for baseline characteristics, and calendar period. Of 694 patients, 84 (12%) died. In adjusted analyses, patients treated with a first-generation PI (hazard ratio [HR] 1.9, p = 0.04) or nevirapine (HR 2.0, p = 0.046) had twice the risk of death compared with those receiving a newer PI. Survival for patients treated with efavirenz did not differ from those receiving a newer PI (HR 1.1, p = 0.8). Greater disease severity (HR 1.7, p = 0.03), hepatitis C virus (HCV; HR 1.6, p = 0.05), and depression (HR 2.0, p = 0.007) were independent predictors of increased mortality. This study demonstrates significant improvement in survival among patients initiating HAART with newer PIs compared to first-generation PIs or nevirapine, and highlights the complexity of patient factors affecting the clinical outcomes of treatment.