OBJECTIVES: Research has consistently demonstrated the effectiveness of antiretroviral therapy (ART) in reducing HIV-related morbidity and mortality.  Current guidelines for the treatment of HIV identify specific combination regimens with medications from two different drug classes.  The objective of this study was to assess compliance with these guidelines among treatment-naïve individuals.  METHODS: Mississippi Medicaid prescription claims data (1/2008 10/2011) were analyzed for beneficiaries who met eligibility criteria: age >17, not pregnant, and enrolled in Medicaid for at least three months prior to the index prescription date.  Beneficiaries were considered treatment-naïve and starting initial therapy if no ART claims existed for at least three months prior to the first ART claim.  We defined a guideline-adherent ART regimen as use of a minimum of three drugs including two nucleoside reverse transcriptase inhibitors (NRTIs) in combination with one protease inhibitor (PI) or one nonnucleoside reverse transcriptase inhibitor (NNRTI) between July 2008 and December 2010.  Between January 2010 and November 2011, a guideline-adherent ART regimen could also include two NRTIs in combination with one integrase inhibitor.  RESULTS: A total of 604 beneficiaries met inclusion criteria.  Between July 2008 and December 2009, 39.8% and 25.5% of beneficiaries were on an NNRTI-based regimen and PI-based regimen, respectively.  Additionally, 4.4% met more than one guideline simultaneously.  Approximately 30.3% were prescribed a medication regimen that was not in accordance with guidelines.  Between January 2010 and October 2011, 38.8% and 24.1% of beneficiaries were on an NNRTI-based regimen and PI-based regimen, respectively.  Additionally, 5.3% met more than one guideline simultaneously.  Approximately 25.5% were prescribed a medication regimen that was not in accordance with guidelines.  CONCLUSIONS: During the study period, the majority of beneficiaries were in accordance with treatment guidelines for initial therapy for treatment-naïve patients with minimal temporal changes across the three primary combination regimens.