Background While living with others has been associated with improved functional outcome after acute stroke, it is unclear if this affects adherence to stroke prevention measures. Aims We examined the relationship between living arrangements and adherence to antiplatelet therapy assignment and participation status in an international randomized trial for secondary stroke prevention. Method Antiplatelet therapy adherence, trial retention outcomes, and baseline characteristics for participants enrolled in the Secondary Prevention of Small Subcortical Strokes study were compared between those who lived alone vs. with others ( n = 2374). Participant status at end-of-trial was categorized into ( 1 ) on assigned antiplatelet, ( 2 ) off assigned anti-platelet by participant request, or ( 3 ) participant withdrew consent/lost to follow-up. Multivariable multivariate logistic regression was used to identify patient features at entry predictive of participant status at trial end. Results Living arrangement, alone vs. with other(s), was not significantly associated with participant status. Participants enrolled in the United States/Canada (odds ratio 3·1, confidence intervals 2·0–5·0, vs. Latin America), taking more (7+) prescription medications (odds ratio 1·7, confidence intervals 1·1–2·7, vs. 0–2 medications), and scoring lower on the Stroke Specific Quality of Life scale (odds ratio 1·3, confidence intervals 1·1–1·5, per 10 points) were more likely to withdraw or become lost to follow-up in the study vs. completing the study on assigned antiplatelet therapy. Participants enrolled in the United States/Canada (odds ratio 5·0, confidence intervals 2·4–10·0, vs. Latin America) and taking fewer (0–2) medications (odds ratio 1·9, confidence intervals 1·2–3·1 vs. 3–6 medications) were more likely to request discontinuation of assigned antiplatelet medication vs. completing the study. Conclusion Living with others was not independently predictive of protocol adherence in this cohort. Number of medications and Stroke Specific Quality of Life scale score may be more indicative of likelihood of trial participation and acceptance of long-term antiplatelet regimen.