Objective: Cabotegravir long-acting (CAB-LA) administered every 2 months was approved in the USA as pre-exposure prophylaxis (PrEP) for individuals at risk of acquiring human immunodeficiency virus (HIV)-1 infection based on the HIV Prevention Trials Network (HPTN) 083 and HPTN 084 clinical trials, which demonstrated superior reduction in HIV-1 acquisition compared with daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) in men who have sex with men (MSM), transgender women (TGW), and cisgender women. A decision-analytic model was developed to assess the lifetime cost-effectiveness of initiating CAB-LA versus generic oral FTC/TDF for HIV PrEP in the USA from a healthcare sector perspective. Methods: PrEP-eligible adults entered the Markov model receiving CAB-LA or FTC/TDF and could continue initial PrEP, transition to a second PrEP option, or discontinue PrEP over time. Efficacy was taken from the HPTN 083 and HPTN 084 clinical trials. Individuals who acquired HIV-1 infection incurred lifetime HIV-related costs, could transmit HIV onwards, and could develop PrEP-related resistance mutations. Input parameter values were obtained from public and published sources. Model outcomes were discounted at 3%. Results: The model estimated that the CAB-LA pathway prevented 4.5 more primary and secondary HIV-1 infections per 100 PrEP users than the oral PrEP pathway, which yielded 0.2 fewer quality-adjusted life-years (QALYs) lost per person. Additional per-person lifetime costs were $9476 (2022 US dollars), resulting in an incremental cost-effectiveness ratio of $46,843 per QALY gained. Results remained consistent in sensitivity and scenario analyses, including in underserved populations with low oral PrEP usage. Conclusions: Our analysis suggests that initiating CAB-LA for PrEP is cost-effective versus generic daily oral FTC/TDF for individuals at risk of acquiring HIV-1 infection.