Importance: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multi-morbidity where the benefits of continued treatment may not outweigh the harms. Objective: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during a 12-week follow-up period. Design, Setting, and Participants: The OPtimising Treatment for MIld Systolic hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, non-inferiority trial conducted in 69 primary care sites in England. Participants were aged ≥80 years with systolic blood pressure <150mmHg and receiving ≥2 antihypertensive medications, whose primary care physician considered them appropriate for medication reduction. Participants were enrolled between April 2017 and September 2018 and followed-up until January 2019. Interventions: Participants were randomised (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of one drug [intervention], n=282) or usual care, in which no medication changes were mandated (control, n=287). Main outcomes: The primary outcome was systolic blood pressure <150 mmHg at 12-week follow-up. The pre-specified non-inferiority margin was a relative risk (RR) of 0.90 (intervention:control). Secondary outcomes included the proportion of participants in the intervention group maintaining medication reduction and between group differences in systolic and diastolic blood pressure, frailty, quality of life, adverse effects and serious adverse events. Results: Among 569 patients who were randomized (mean age, 84.8; 276 (48.5%) women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure of <150 mmHg at follow-up (Adjusted RR 0.98, 97.5% 1-sided CI 0.92 to ). Of seven pre-specified secondary endpoints, five showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mmHg (95% CI 1.1 to 5.8 mmHg) higher in the intervention group compared to control. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least one serious adverse event (adjusted RR 1.72, 95%CI 0.7 to 4.3). Conclusions and relevance: Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was non-inferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction can be achieved in some older patients with hypertension, without substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes. Trial registration: EudraCT:2016-004236-38; ISRCTN:97503221.