Objectives: The optimal antiretroviral therapy for patients with the M184V/I mutation is not known. The primary objective of this study was to determine the efficacy of various antiretroviral therapies in patients with HIV and the M184V/I mutation based on the number of active antiretroviral agents. Methods: A retrospective chart review was conducted of 100 treatment-experienced patients harboring the M184V/I mutation seen at an urban HIV clinic. Efficacy was classified as percentage of patients with viral suppression defined as HIV RNA viral load <200 copies/mL at last measurement on current antiretroviral therapy, stratified by the number of active antiretroviral agents. Results: The primary outcome of viral suppression occurred in 70.6% (12/17) of patients on <2 active agents, 77.2% (44/57) on 2–2.5 active agents, and 69.2% (18/26) on 3 active agents. No significant difference was found between viral suppression and patients on <2 and 2–2.5 antiretroviral agents (odds ratio = 0.71, 95% confidence interval = (0.21, 2.39), p = 0.8) or between patients on 3 and 2–2.5 active agents (odds ratio = 0.66, 95% confidence interval = (0.23, 1.88), p = 0.7). The most commonly prescribed regimen consisted of a boosted protease inhibitor with an integrase strand transfer inhibitor and two nucleoside reverse transcriptase inhibitors, one of which being lamivudine or emtricitabine. Conclusion: Similar rates of viral suppression were observed in patients regardless of the number of active antiretroviral agents prescribed. Regimens containing less than 3 active agents may maintain virologic suppression in patients with the M184V/I mutation. Further studies are needed to determine optimal antiretroviral therapy for patients with the M184V/I mutation.