OBJECTIVE: The aim of this work was to study weight loss and risk of cardiovascular disease (CVD) or death associated with longer-term phentermine use. METHODS: Using electronic health record data, 13,972 adults were identified with a first phentermine fill in 2010 to 2015, creating exposure categories according to a patient's duration of use (referent: = 3 months). Multivariable linear models were used to compare percent weight loss across categories at 6, 12, and 24 months, and Cox proportional hazards models were used to compare risk of composite CVD or death, up to 3 years after starting phentermine. RESULTS: The cohort was 84% female and 45% white, with a mean (SD) baseline age 43.5 (10.7) years and BMI of 37.8 (7.2) kg/m(2) . In multivariable models, longer-term users of phentermine experienced more weight loss; patients using continuously for > 12 months lost 7.4% more than the referent group at 24 months (P < 0.001). The composite CVD or death outcome was rare (0.3%, 41 events), with no significant difference in hazard ratios between groups. CONCLUSIONS: Greater weight loss without increased risk of incident CVD or death was observed in patients using phentermine monotherapy for longer than 3 months. Despite the limitations of the observational design, this study supports the effectiveness and safety of longer-term phentermine use for low-risk individuals.