Rationale: Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. Objective: To evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task-shifting strategy for hypertension control (TASSH) plus HIC on systolic BP reduction among patients with uncontrolled hypertension in Ghana. Methods and Findings: Using a pragmatic cluster-randomized trial, 32 community health centers within Ghana's public healthcare system were randomly assigned to either HIC alone or TASSH+HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28 2012 and June 11 2014 and followed up to October 7 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits while TASSH+HIC comprised cardiovascular risk assessment; lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months delivered by trained nurses within the healthcare system. The primary outcome was change in systolic BP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and BP control at 12 months; and sustainability of systolic BP reduction at 24 months. Of the 757 patients (389 in HIC and 368 in TASH+HIC groups), 85% had 12 month data available [60% women, mean BP 155.9/89.6]. In intention-to-treat analyses adjusted for clustering, the TASSH+HIC group had a greater SBP reduction (20.4 mmHg; 95% CI -25.2 to -15.6) than the HIC group (16.8 mmHg; 95% CI -19.2 to -15.6) with a statistically significant between-group difference of 3.6 mmHg [95% CI -6.1 to -0.5; p = 0.021]. Blood pressure control improved significantly in both groups (55.2%; 95% CI 50.0 to 60.3 for the TASSH+HIC group versus 49·9; 95% CI 44.9 to 54.9 for the HIC group) with a non-significant between-group difference 5.2% ( 95% CI =-1.8 to 12.4; p=0.29). Similarly, lifestyle behaviors did not change appreciably for both groups. Twenty-one adverse events were reported (9 and 12 in the TASSH+HIC and HIC group respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional cost-benefit, if any, of the TASSH+HIC group. Conclusions: Provision of health insurance coverage plus a nurse-led task-shifting strategy was associated with a greater reduction in systolic BP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost-benefit analysis.