OBJECTIVES: Current U.S. Department of Health and Human Services (DHHS) HIV treatment guidelines recommend that HIV patients initiate first-line antiretroviral therapy (ART) with one of four “preferred” regimens:  efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC), ritonavir-boosted atazanavir + tenofovir/emtricitabine (ATV/r+TDF/FTC), ritonavir-boosted darunavir + tenofovir/emtricitabine (DRV/r+TDF/FTC), or raltegravir + tenofovir/emtricitabine (RAL+TDF/FTC). Adherence is critical to the success of ART in suppressing viral load and avoiding virological failure and development of drug resistance.  This study compared ART adherence between preferred ART regimens in a real-world setting. METHODS: Retrospective study using U.S. Medicaid administrative health care claims from 15 states. Subjects were HIV patients aged 18-64 years who were enrolled in Medicaid and initiated, between January 1, 2007 and September 30, 2011, a first-line ART regimen “preferred” under U.S. DHHS HIV treatment guidelines published in March 2012.  Patients were classified by ART regimen and were required to be continuously enrolled for 6 months before and ≥3 months following ART initiation. Follow up lasted from ART initiation until a ≥30 day gap in initiated ART, introduction of a new ART medication, or disenrollment.  Adherence, defined as the proportion of days covered by ART medication during follow up (dichotomized at ≥80%), was evaluated using multivariable logistic regressions that adjusted for demographic and clinical factors. RESULTS: Sample included 1,979 patients initiating EFV/TDF/FTC (n=1,259), ATV/r+TDF/FTC (n=498), DRV/r+TDF/FTC (n=143), or RAL+TDF/FTC (n=79); mean age by regimen ranged from 40.1 to 42.1 years and proportion male from 44.1% to 55.4%. Compared with patients initiating EFV/TDF/FTC, odds of adherence ≥80% were significantly lower in DRV/r+TDF/FTC patients (odds ratio [OR]=0.56, p=0.045) and trended lower in RAL+TDF/FTC patients (OR=0.666, p=0.273) and ATV/r+TDF/FTC patients (OR=0.904, p=0.610).  CONCLUSIONS: Among patients initiating a DHHS guideline-preferred first-line ART regimen, the odds of adherence were not the same for all regimens.  Further research should explore the reasons for differences in adherence levels between “preferred” ART regimens.