Although switching of antiretroviral therapy (ART) is a valid approach for addressing treatment failure in patients with human immunodeficiency virus (HIV), ART changes among those who are well maintained on their current regimens may lead to the development of new side effects or resistance. To examine the effect of first-line regimen switching on subsequent health care utilization and cost among stable HIV patients. This was a retrospective claims data study of adult patients with HIV who initiated ART between 2007 and 2013 and had been treated with their initial regimens for at least 6 continuous months. Those with evidence of pregnancy or HIV-2 were excluded. Patients who underwent an ART change were assigned to a switcher cohort; a nonswitcher cohort was then generated by matching up to 20 nonswitchers for each switcher, with replacement. The index date was the date of the first ART change for switchers and was the claim date closest to the corresponding switcher's switch date for nonswitchers. Patient characteristics at baseline and post-index annualized health care utilization and costs were analyzed descriptively and with multivariable models. Analyses were performed in the full population and among patients designated as virologically stable (had undetectable viral ribonucleic acid [RNA] for 90 days pre-index) and virologically and clinically stable (had undetectable viral RNA and no apparent clinical reason for switching ART). The study population consisted of 6,983 individuals, which included 927 switchers (168 virologically stable; 55 virologically+clinically stable), who were matched with replacement with 18,511 nonswitcher comparators. The switcher cohort was 88.8% male (mean age 43.8 years). Mean preindex and follow-up treatment durations for switchers and nonswitchers were 1.8 years and 1.5 years, respectively; demographic characteristics, pre-index treatment duration, and follow-up duration were similar between cohorts. Significantly more nonswitchers than switchers had a first-line efavirenz-based regimen (67.2% vs. 47.8%, P < 0.001). In the virologically stable subset, follow-up annualized health care utilization for switchers versus nonswitchers, respectively, was 14.8 versus 12.3 ambulatory visits (P < 0.05), 0.8 versus 0.9 emergency department visits (P = 0.652), and 0.05 versus 0.05 inpatient hospitalizations (P = 0.915). Follow-up annualized health care costs were $37,120 for switchers versus $31,771 for nonswitchers (P < 0.05), with the difference driven largely by pharmacy costs. Multivariable-adjusted follow-up annualized health care costs were 8.9% higher among switchers versus nonswitchers (P < 0.01), and switchers also had a shorter time to subsequent ART regimen change (P < 0.001). Results were similar for the virologically+clinically stable subset. In this large, real-world population, stable patients with HIV who switched from their first-line ART regimens had significantly higher health care costs than those who did not change therapies, suggesting that ART regimen changes may be costly and should be undertaken only when clinically warranted. This work was funded by Bristol-Myers Squibb (BMS), which participated in the design of the study, interpretation of the data, revision of the manuscript, and the decision to submit the manuscript for publication. Rosenblatt is an employee and stock owner of BMS; Villasis-Keever was an employee of BMS at the time this study was conducted and is currently an employee of Janssen. Buikema is an employee and stock owner of Optum, and Seare, Bengston, Johnson, and Cao are employees of Optum, which was contracted by BMS to conduct the study. Optum contracts with pharmaceutical companies, such as Janssen, Merck, EMD Serano, GlaxoSmithKline, and Gilead, to conduct research in HIV. Optum is also a subsidiary of a health plan that has interest in managing the health and associated costs of patients with HIV. Study concept and design were contributed by Rosenblatt and Buikema, along with the other authors. Cao and Johnson took the lead in data collection, along with Buikema, Seare, and Bengston. Data interpretation was performed by Buikema, Seare, Bengston, and Villasis-Keever. The manuscript was written by Buikema and Bengston, along with Rosenblatt, Seare, Johnson and Villasis-Keever, and revised by Rosenblatt, Villasis-Keever, and Johnson, along with the other authors.