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).  While the clinical value of these regimens is well-supported, there are limited data on their relative economic value.  This study compared healthcare expenditures between the four “preferred” ART regimens. METHODS: Retrospective study using 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. Per-patient-per-month (PPPM) total mean health care expenditures during follow up were evaluated using log-linear regressions. Log-expenditures were retransformed via ‘smearing.’ Inference was based on recycled prediction with 500 bootstrap repetitions. 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%. PPPM total mean healthcare expenditures for EFV/TDF/FTC patients were $3,476.  In comparison, PPPM total mean healthcare expenditures were significantly higher for DRV/r+TDF/FTC patients (by $2,155, 95% CI =$1,364 to $3,074, p<0.01), ATV/r+TDF/FTC patients (by $1,379, 95% CI=$951 to $1,971, p<0.01) and RAL+TDF/FTC patients (by $1,479, 95% CI=$544 to -$2,526, p<0.01) than for EFV/TDF/FTC patients. CONCLUSIONS: This study found significant differences in health care expenditures between HIV patients initiating different ART regimens “preferred” under current U.S. treatment guidelines.