BACKGROUND: In US treatment guidelines, efavirenz (EFV) is the preferred non-nucleoside reverse transcriptase inhibitor (NNRTI) for first-line treatment of HIV. In the ECHO and THRIVE trials comparing EFV with another NNRTI, rilpivirine (RPV), both medications had similar rates of virologic suppression at 96-weeks; however, RPV had higher rates of virologic failure and drug resistance and lower rates of discontinuation due to adverse events. OBJECTIVES: To estimate the cost-effectiveness of EFV versus RPV in first-line HIV treatment in the US. METHODS: A Markov model with 14 health states was constructed to estimate 10-year costs and clinical outcomes from a US payer perspective for antiretroviral naïve HIV patients initiating EFV or RPV.  First-line efficacy data came from 96-week results of the ECHO and THRIVE trials, which compared EFV and RPV, both in combination with two nucleos(t)ide reverse transcriptase inhibitors. Other clinical inputs, mortality rates and costs (2011 US$) came from published sources. Subsequent therapy lines (second, third, non-suppressive) were based on US treatment guidelines and common to both treatment arms. Robustness of study results was assessed in sensitivity analyses that varied model inputs by ±25%. RESULTS: In the base case, total costs over 10 years were lower for EFV versus RPV ($214,031 versus $222,090).  Life expectancy (8.44 years) and life years without AIDS (8.40 years) were the same and life years in virologic suppression were similar (EFV= 7.87 years, RPV=7.86 years).  EFV was modestly cost-saving versus RPV in terms of incremental cost-effectiveness per life-year gained, per life-year gained in viral suppression, and per life-year gained without AIDS.  In sensitivity analyses, EFV remained cost-saving versus RPV more than 90% of the time, demonstrating the robustness of study results. CONCLUSIONS: Over a 10-year time horizon, EFV was predicted to be modestly cost-saving compared with RPV in HIV patients initiating first-line treatment in the US.