Background Non-adherence is a problem that particularly affects those with chronic diseases. Studying causes for not following the treatment is necessary to choose the best intervention to improve non-adherence. Objective Analyze how the intentionality of non-adherence modulates the effects of professional intervention in patients with hypercholesterolemia. Setting: Community pharmacies and primary care centres in Spain. Methods A 6-month randomized controlled trial was conducted in 46 community pharmacies and 50 primary care centres in Spain. Adherence to statin therapy was measured with the Morisky-Green-Levine test. Non-adherence was classified based on the intentionality. Results 746 Patients were recruited for the study (465 non-adherent and 281 adherent). Of those, 237 were randomly assigned to the intervention group and 228 to the non-intervention group. The 56.5% of non-adherent patients were classified as unintentional non-adherents and 43.5% as intentional non-adherents. More patients in the intervention group finished being adherent compared with the non-intervention group (+ 17.2% for intentional non-adherents and + 27.4% for unintentional non-adherence). The percentage of patients in the intervention group who completed the study as adherent was higher among those who previously had unintentional non-adherence (66.4%) compared to those with intentional non- adherence (55.3%) (p < 0.001). Conclusion Intervention provided to patients with unintentional non-adherence was more effective than intervention provided to patients with intentional non- adherence.