Discontinuation of medication use constitutes a major barrier to adequate control of high blood pressure. We examined the effect of an array of potential predisposing, enabling and reinforcing factors on the discontinuation of newly prescribed antihypertensive medications. We conducted a prospective cohort study through a network of 173 pharmacies across Canada where were identified individuals newly prescribed an antihypertensive monotherapy. We interviewed participants by telephone four times to obtain information for a minimum duration of 18 months after entry into the cohort. We analyzed data using a multivariate proportional hazard model. Of 682 eligible participants, 43.3% had discontinued their initial medication at the end of the observation period. Individuals more likely to discontinue their initial medication were those who perceived side effects from this medication [Hazard Ratio (HR) = 1.91; 95% Confidence Interval (CI) 1.47-2.47). Individuals with medication insurance coverage were less likely to discontinue (HR = 0.74; 95% CI 0.55-0.99). Persistence with newly prescribed medications could be improved by selecting antihypertensive medications containing fewer side effects and by lifting economic barriers to drug treatment.