OBJECTIVES: Guidelines recommend that patients with HIV infection who are naïve to treatment receive two nucleoside reverse transcriptase inhibitors (NRTI) plus a third agent which may be a non nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI), or integrase inhibitor (II). This study examined treatment patterns and drug treatment costs in such patients. METHODS: Retrospective analysis of pooled US health insurance claims data for commercially insured (Pharmetrics/I3/Thomson) and Thomson Medicaid patients, 2007–2009. RESULTS: Data from 14,002 treatment-naïve patients were collected. 6,801 patients (49%) started on an NNRTI (of which 99.8% on efavirenz, mainly as part of a fixed-dose combination), 5,966 (43%) on a PI and 1,235 (9%) on an II or another third agent. As expected due to the teratogenic potential of efavirenz, substantially fewer women aged <40 years started NNRTI treatment (32.5% vs 60% starting a PI). Of all patients who started on efavirenz, 66% remained on this initial treatment at 1 year. Of patients who switched to another regimen after discontinuing efavirenz, 85% changed to a PI-based regimen. At the start of efavirenz treatment, mean daily drug cost (including 2 NRTIs) was 46 USD. For patients who switched subsequently to a PI-based regimen, mean daily drug cost rose by 51% to 70 USD. Corresponding values from the individual databases were consistent. CONCLUSIONS: Within one year after initiation of therapy, many patients discontinue efavirenz. When changing to another regimen, the majority switch to a PI, with an associated rise in costs. The study highlights opportunities in the current HIV treatment-naïve market and the need for new third agents which are as effective but better tolerated than efavirenz, and may be used in women of childbearing potential. Such agents may alleviate the need to start with and/or delay the switch to more expensive treatments, potentially reducing HIV treatment costs.