Background: Angiotensin-converting-enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) are recommended in diabetic and proteinuric nondiabetic chronic kidney disease (CKD). However, therapy with ACEi/ARBs is associated with an increased risk of hyperkalemia. For the management of chronic hyperkalemia, physicians are faced with the important clinical decision of whether to discontinue ACEi/ARBs or continue them despite a risk of hyperkalemia reoccurring. The aim of this study is to evaluate the effect of discontinuing ACEi/ARBs after an episode of hyperkalemia in patients with CKD. Methods: We performed a retrospective cohort study using administrative health data from Manitoba, Canada. All adults (≥ 18 years old) with an episode of de novo hyperkalemia (defined as serum potassium ≥ 5.5 mmol/L) and CKD who were current ACEi/ARB users at the time of their hyperkalemia episode were included. We examined the association between ACEi/ARB exposure and study outcomes in patients with an episode of hyperkalemia using Cox proportional hazards regression models where our primary analysis assessed continuation of ACEi/ARB versus discontinuation as a time-dependent variable. In sensitivity analyses, this association was assessed using intention-to-treat, as well as dose reduction analyses. Results: In our cohort, 34,317 people who had an episode of hyperkalemia were identified, of which 8,534 had CKD and were current ACEi/ARB users at baseline. Ninety days after the episode of hyperkalemia, 7,203 surviving patients were included for analyses. In time-dependent analysis, ACEi/ARB discontinuation was associated with a more than 2-fold higher risk of both all-cause [hazard ratio (HR) 2.68, 95% CI: 2.48-2.89] and cardiovascular mortality [HR 2.42, 95% CI 2.10-2.77]. Intention to treat analyses showed similar results. Suboptimal dose use was associated with increased all-cause mortality (adjusted HR 1.21, 95% CI 1.10-1.33) compared to maximal daily dose. Conclusion: ACEi/ARB discontinuation was associated with a more than 2-fold higher rate of all-cause mortality, compared with patients who continued ACEi/ARB. Patients on suboptimal doses had worse outcomes compared to those receiving a maximal daily dose.