Purpose To analyze patterns of antihypertensive drug use among new users in a Southern European population, and identify patient- and treatment-related factors that influence persistence. Methods This is a retrospective observational study of new antihypertensive drug users aged ≥40 years in Aragón, Spain. Information on antihypertensive drugs (2014–2016) prescribed and dispensed at pharmacies via the public health system were collected from a regional electronic population-based pharmacy database. Persistence was assessed using the gap method. Kaplan-Meier and Cox regression analyses were conducted to analyze patterns of use and factors that influence persistence. Results The 25,582 new antihypertensive drug users in Aragón during the study period were prescribed antihypertensive drugs in monotherapy (73.3%), fixed combination (13.9%), free combination (9.1%), or other (3.7%). One in five received antihypertensive drugs within 15 days of the prescription date, but not after. During the first year of follow-up, 38.6% of the study population remained persistent. The likelihood of treatment discontinuation was higher for participants who were male, aged ≥80 years, and received an antihypertensive drug in monotherapy compared with fixed combination. Conclusion Overall persistence with antihypertensive therapy was poor, and was influenced by the sex, age and type of therapy. Fixed combinations appear to be a good choice for initial therapy, especially in patients with a higher risk of discontinuation. Nonetheless, adverse drug effects and the patient’s preferences and clinical profile should be taken into account.