Discontinuation of drug use constitutes a major barrier to adequate control of high blood pressure. Although various factors may be associated with discontinuation of treatment, so far, very few causal associations have been studied. OBJECTIVES: To examine the effect of an array of potential predisposing, enabling and reinforcing factors on discontinuation of initial antihypertensive medication. METHODS: We conducted a prospective cohort study through a network of 173 pharmacies across Canada who identified individuals starting a new antihypertensive medication as a monotherapy. We excluded pregnant women, individuals who were taking other antihypertensive medications at the same time, and those who took medications for chronic heart failure, or angina. We interviewed subjects by telephone four times over a 36 month period. We analyzed data using a CoxÕs proportional hazard model. RESULTS: Out of 682 eligible subjects, 43% 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 with the initial medication (Adjusted Hazard Ratio (AHR)= 1.91; 95% Confidence interval (CI)= 1.47-2.48) and those who believed the antihypertensive medication had no effect (AHR= 1.33; 95% CI= 1.03-1.72). Insurance coverage for antihypertensive medication had a protective effect (AHR= 0.74; 95% CI= 0.55-0.99). CONCLUSIONS: Persistence with newly prescribed medications could be improved by selecting antihypertensive medications with fewer side effects, by changing misleading perceptions of patients about their treatment, and by removing economical barriers.