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BACKGROUND: Despite overall improvements in cardiovascular‐disease therapies and outcomes, medication nonadherence remains an important barrier to effective secondary prevention of atherothrombotic disease. HYPOTHESIS: Long‐term medication adherence in outpatients with stable atherothrombotic disease is impacted by demographic and clinical factors. METHODS: We examined data from the prospective international Reduction of Atherothrombosis for Continued Health (REACH) Registry. Analyses were derived from 25 737 patients with established atherothrombotic disease with complete adherence data at enrollment and at year 4. Adherence was defined as patients' self‐report of taking medications based on class I American College of Cardiology/American Heart Association guidelines for secondary prevention as defined, including antiplatelet agents, statins, and antihypertensive medications. RESULTS: Among patients with atherothrombotic disease, 12 500 (48.6%) were deemed adherent to guideline‐recommended medications. Adherent patients were younger, white, and had less polyvascular disease. Hispanic and East Asian patients were less likely to be adherent as compared with white patients (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.59‐0.88; and OR: 0.67, 95% CI: 0.53‐0.83, respectively). Patients who had a nonfatal MI or underwent coronary angioplasty/stenting during follow‐up were more likely to be adherent compared with patients without these events (OR: 1.73, 95% CI: 1.25‐2.38; and OR: 2.15, 95% CI: 1.72‐2.67, respectively). On the other hand, nonfatal stroke during follow‐up was inversely associated with adherence (OR: 0.77, 95% CI: 0.61‐0.97). CONCLUSIONS: Using a large international registry of outpatients with atherothrombotic disease, we found that age, region, race/ethnicity, and incident cardiovascular events were predictive of long‐term guideline adherence for secondary prevention, suggesting that certain patient groups may benefit from targeted interventions to improve adherence.