Background: US national guidelines call for cost-conscious practices including the selection of antiretroviral therapy. Objective: The objective is to analyze the relative cost-effectiveness of contemporary antiretroviral therapy in real-world clinical settings. Design: Observational cohort study. Methods: Retrospective follow-up study of treatment-naive persons living with HIV initiating antiretroviral therapy (ART) between January 2007 and December 2012 at an academically affiliated HIV clinic was conducted. Analysis was restricted to patients with the five most commonly prescribed regimens (N= 491). Patients were followed until December 14 to determine the durability of the initial regimen prescribed; median durations were calculated using Kaplan-Meier survival analyses. The average 340b price of the ART regimen 30-day supply was used for cost. Sensitivity analyses were performed adjusting for missing data and pricing indices and using mean durability (=1 SD). Results: Initial regimens contained emtricitabine and tenofovir, along with a third drug. Median durability was shortest for ritonavir-boosted atazanavir (31.9 months) and longest for ritonavir-boosted darunavir and raltegravir (both 47.8 months). All regimens were dominated, meaning less durable and more costly, relative to efavirenz (710.64/month) and raltegravir-based regimens (1075.03/month). These findings were reproduced in sensitivity analysis, although rilpivirine became a valuable option in some scenarios. Relative to the efavirenz-based regimen, raltegravir had an incremental cost of 47/month of additional therapy. Conclusion: In this sample, raltegravir and efavirenz-based regimens are the most costeffective options for treatment-naive patients. Sensitivity analyses suggest rilpivirine is a reasonable choice in limited scenarios. These findings are relevant given changes in recommended regimens for treatment-naive persons, which include raltegravir and darunavir but exclude efavirenz and rilpivirine-based regimens. Summary: Of five commonly prescribed regimens for treatment-naive HIV patients in one clinic (2007-2012), emtricitabine and tenofovir with efavirenz and raltegravir were the only consistently cost-effective options; the rilpivirine-based regimen was valuable in limited scenarios. Further data on the comparative effectiveness of efavirenz and rilpivirine are needed before they are abandoned.