Background. Pharmacological non-adherence in chronic diseases is 40–65%. No predictive profile of non-adherence exists in patients with multiple chronic diseases. Our study aimed to quantify the prevalence of non-adherence to pharmacological treatment and its associated factors in patients who visit pharmacies in Spain. Methods. This observational cross-sectional study included patients with one or more chronic diseases. The variables analyzed were demographics, diseases involved, self-medication, information about disease, and lifestyle. The main variable was adherence using the Morisky–Green test. A total of 132 pharmacies collaborated, providing 6327 patients representing all Spain regions (April–December 2016). Bivariate and multivariate analyses were performed and the area under the receiver operating characteristic (ROC) curve was calculated. Results. Non-adherence was 48.4% (95% confidence interval (CI): 47.2–49.7%). The variables that reached significance in the multivariate model were: difficulty in taking medication, self-medication, desire for more information, smoking, lower physical activity, younger age and number of chronic treatments. Discrimination was satisfactory (area under the ROC curve = 70%). Our study found that 50% patients was non-adherent and we obtained a profile of variables associated with therapeutic non-adherence. Conclusions. It is cause for concern that in patients with multiple diseases and taking multiple medications, there is an association between non-adherence, self-medication and worse lifestyle.