Acne is a common chronic disease that typically requires prolonged treatment. Several small studies conducted over the past few years suggest that adherence to acne medications is often poor. In addition, data regarding the factors that positively or negatively impact adherence in patients with acne are sparse. This study utilized a simple, validated questionnaire (ECOB, Elaboration d’un outil d’evaluation de l’observance des traitements medicamenteux) to assess the risk of poor adherence in a large worldwide cohort of acne patients (n = 3339) from three major geographic regions [the Americas (n = 952), Europe (n = 1196), and Asia (n = 1191). In addition, information about patient and treatment characteristics was collected to identify factors that correlated with adherence. Overall, there was a poor adherence rate of 50% in this study; this varied by region, with significantly worse adherence in Europe versus Asia and America (poor adherence rates of 58%, 48%, and 43%, respectively, P < 0.0001). To provide insight into factors that affect medication-taking behavior in acne, adherence was analyzed by the type of treatment (a combination of topical and systemic, topical only, oral isotretinoin). Among patients taking a combination of both systemic and topical therapy, 60% (n = 944) of patients had poor adherence to at least one treatment as defined in the study protocol. In this group, there was a higher proportion of patients who had poor adherence to systemic treatment versus topical treatment (54% vs. 44%, respectively). Among patients treated with topical therapy only, poor adherence occurred in 40% (n = 356) of cases. A total of 46% (n = 325) of patients using oral isotretinoin therapy had poor adherence. Multivariate analysis showed that poor adherence was independently correlated with young age (most strongly with <15 years but also in the age group from 15 to 25 years), the occurrence of side effects, lack of improvement as evaluated by dermatologist, previous systemic therapy, lack of knowledge about acne treatment, consultation with a primary care physician, and lack of patient satisfaction with treatment. Factors that had a positive effect on adherence were more severe acne, use of cosmetics (moisturizers, cleansers), use of either topical therapy alone or isotretinoin, good clinical improvement as evaluated by the dermatologist, patient satisfaction with therapy, and knowledge of acne treatment.