Metabolic abnormalities associated with the treatment of human immunodeficiency virus (HIV) infection are well-recognized problems that increase cardiovascular risk. As a result of the complexity of treating both HIV- and antiretroviral-related comorbidities, strategies that improve adverse drug events while maintaining viral control are in critical need. Although guidelines have somewhat helped in the general approach and in first-line strategies for managing dyslipidemia in patients receiving antiretrovirals, a paucity of data exist to guide clinicians in treating patients whose conditions are refractory to first-line options or who are at substantial risk for cardiovascular events. Further complicating the choice of lipid-lowering strategy is the lack of randomized controlled data from the HIV-affected population and a concern about clinically significant drug-drug interactions. We describe an HIV-infected patient with efavirenz-associated dyslipidemia at very high cardiovascular risk who had not achieved his primary or secondary lipid goals despite 2 years of treatment in a lipid specialty clinic. Lipid control was accomplished in 10 weeks with a targeted, stepwise approach of switching efavirenz to nevirapine, followed by rosuvastatin 20 mg/day, which was sustained for at least 10 months. Of most importance, this outcome was achieved without any clinically significant alteration in virologic or immunologic control. This case report highlights the potential for a pharmacist-guided, multistep approach that addresses HIV-related dyslipidemia and incorporates the pharmacokinetic literature to guide lipid-lowering therapy and promote the attainment of goals based on current standards of care.