Today, near normal life expectancy among people living with HIV infection, translates into life-long exposure to antiretroviral treatment (ART). Reducing drug burden without compromising efficacy via a 2-drug regimen could reduce ART-associated long-term toxicity, and potentially generate significant savings to the health care system compared to traditional 3-drug regimens (3DR). Two recent phase III trials (GEMINI 1&2) have demonstrated the non-inferiority of dolutegravir plus lamivudine (DTG+3TC) versus DTG plus tenofovir disoproxil and emtricitabine (TDF/FTC), in achieving virologic suppression at week 48. A network meta-analysis (NMA) comparing DTG/3TC with other ART regimens recommended by the US Department of Health and Human Services showed numerical differences in efficacy and safety versus 3DRs. This study aimed to evaluate the cost-effectiveness of DTG/3TC in the US, in treatment naïve HIV-infected patients. A cost-utility analysis using a hybrid decision-tree and Markov model was run probabilistically to estimate total lifetime costs and quality-adjusted life years (QALYs) of DTG/3TC versus recommended regimens. Health states were defined by viral load and CD4-cell count. Efficacy and safety data were derived from GEMINI trials and the NMA. Costs (inflated to 2017 USD) were obtained from published literature and discounted at 3% annually. Current branded drug acquisition prices were included for all ART regimens. Versus most comparators (including Bictegravir/TAF/FTC), DTG/3TC was dominant, with incremental QALYs ranging from 0.016 to 0.203 across these comparisons. Further, driven by the lower cost of DTG/3TC, significant cost-savings were observed across all comparisons (cost savings of $48,047 to $157,080). Assuming a willingness-to-pay threshold of $100,000/QALY, the likelihood of cost-effectiveness was estimated to be >99% across all comparisons. Results suggest that DTG/3TC is a highly cost-effective regimen for US payers, providing similar efficacy to recommended regimens, while offering the potential for marginal QALY gains and significant cost savings in the treatment of naïve HIV-patients.