BACKGROUND: Obesity prevalence exceeds 40% in the US adult population, posing a substantial burden on the health care system. Antiobesity medication (AOM) is recommended for obesity management. However, little evidence exists estimating the economic impact of AOMs on health care costs over time. OBJECTIVE: To estimate the impact of AOMs indicated for long-term therapy on short-term direct medical costs, by obesity class, in a commercially insured population. METHODS: For this retrospective cohort study, we used the IBM MarketScan Commercial Claims and Encounters Database to capture health care utilization between January 1, 2015, and December 31, 2019. Adults aged 18-63 years with a body mass index greater than or equal to 30 kg/ m2 were categorized into 2 cohorts based on new AOM usage at cohort entry. New AOM users were taking 1 of 4 AOMs currently approved by the US Food and Drug Administration for long-term therapy, with greater than 112 days supply of medicine within 12 months after treatment initiation. AOM nonusers were those not taking an AOM indicated for long-term therapy during the baseline or follow-up period. We used difference-in-differences estimation to calculate the change in average annual total health care costs and cost of medications (excluding AOMs) over a 2-year follow-up period using inverse probability of treatment-weighted estimates. RESULTS: The study population included 219,971 patients, 1,405 AOM users and 218,566 AOM nonusers. Over 2 years, patients on treatment were more than twice as likely to be classified into a lower obesity class than AOM nonusers. Although the average yearly direct cost of care increased for both treatment groups in the first year of follow-up, by year 2, costs for untreated patients continued to rise while costs for patients on therapy remained stable or declined. The difference-in-differences of medication cost (excluding AOMs) and total health care cost (excluding AOMs) across all 3 obesity classes in year 2 ranged from $1,321 to $1,952 and $1,323 to $2,766, respectively, indicating a cost savings. Total cost of care, inclusive of AOMs, followed a similar trend. CONCLUSIONS: Use of AOMs is associated with the odds of moving to a lower obesity class and a general stabilization or reduction in health care costs in year 2 of follow-up. When considering change in health care costs over time, use of AOMs may be an effective strategy to mitigate the rising health care costs associated with obesity.