BACKGROUND: Initial medication non-adherence is highly prevalent in primary care but no previous studies have evaluated its impact on the use of healthcare services and/or days on sick leave. AIM: To estimate the impact of initial medication non-adherence on the use of healthcare services, days of sick leave, and costs overall and in specific medication groups. DESIGN AND SETTING: A 3-year longitudinal register-based study of all primary care patients (a cohort of 1.7 million) who were prescribed a new medication in Catalonia (Spain) in 2012. METHOD: Thirteen of the most prescribed and/or costly medication subgroups were considered. All medication and medication subgroups (chronic, analgesics, and penicillin) were analysed. The number of healthcare services used and days on sick leave were considered. Multilevel multivariate linear regression was used. Three levels were included: patient, GP, and primary care centre. RESULTS: Initially adherent patients made more use of medicines and some healthcare services than non-adherent and partially adherent patients. They had lower productivity losses, producing a net economic return, especially when drugs for acute diseases (such as penicillins) were considered. Initial medication non-adherence resulted in a higher economic burden to the system in the short term. CONCLUSION: Initial medication non-adherence seems to have a short-term impact on productivity losses and costs. The clinical consequences and long-term economic consequences of initial medication non-adherence need to be assessed. Interventions to promote initial medication adherence in primary care may reduce costs and improve health outcomes.