The study objective was to compare the long-term incidence and risk of mortality and cardiovascular outcomes in patients with hypertension initiating bisoprolol, other β-blockers or other antihypertensive therapies. Cohort analysis using UK Clinical Practice Research Datalink (CPRD). Adult patients with first diagnosis of hypertension recorded between 2000 and 2014, with ≥365 days of registration to first event and initiating monotherapies of bisoprolol, other β-blockers or drugs other than β-blockers within 6 months of diagnosis were included. Incidence rates (IR) for each treatment cohort were compared using adjusted hazard ratio (HR) and 95% confidence intervals (CI) obtained from Cox regression analyses. Of 100,066 patients included, 539 were prescribed bisoprolol, 3701 other β-blockers, and 95,826 drugs other than β-blockers. Patients receiving bisoprolol had significantly increased survival from 2 up to <15 years (HR for <15 years 0.34; 95% CI 0.18–0.67) versus other β-blockers, and from 5 to <15 years (HR for <15 years 0.52; 95% CI 0.27–1.00) versus drugs other than β-blockers. Over time, the risk of arrhythmia was higher in the bisoprolol cohort versus other β-blockers, and risks of arrhythmia and angina were higher versus drugs other than β-blockers. No differences in the risk of embolism, stroke, and myocardial infarction (MI) were found between cohorts. Over time, mortality and cardiovascular outcome IRs decreased in each cohort. In conclusion, bisoprolol showed sustained benefit on survival, evident from 2 years after treatment initiation versus other β-blockers, and from 5 years versus drugs other than β-blockers, providing long-term evidence supporting the use of bisoprolol in patients with hypertension in primary care.