AIMS:The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. METHODS:The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein-platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. RESULTS:A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. CONCLUSIONS:The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel.