Purpose: Amiloride reduces functional neurological deficits and neuronal damage in animal models of multiple sclerosis (MS). We investigated whether amiloride use was associated with reduced risk of incident MS and of MS hospitalization and death in humans. Methods: We conducted two propensity score-matched cohort studies, linking nationwide registry data on filled drug prescriptions, diagnostic information, and covariates. First, we compared rates of incident MS in new users of amiloride and new users of an active control treatment, thiazide diuretics. Second, rates of hospitalizations for MS and of death were compared between users of amiloride and thiazides in a cohort of MS patients. Treatment groups were matched 1:4 on propensity scores that included a wide range of covariates, and Cox regression was used to estimate hazard ratios (HRs). Results: Comparing 36659 users of amiloride and 177031 users of thiazides, there were 19 cases of incident MS during 92548 person-years of follow-up among amiloride users and 81 cases during 567599 person-years of follow-up among thiazide users. There was no significantly decreased risk of MS associated with amiloride use (HR 1.34, 95%CI 0.81-2.20). In the cohort of MS patients, amiloride use was not associated with significantly decreased risk of MS hospitalization (HR 1.11, 95%CI 0.79-1.59) or death (HR 1.38, 95%CI 0.83-2.28). Conclusion: Amiloride use was not associated with significantly decreased risk of incident MS or hospitalizations and death among patients with MS. Because amiloride users were represented by older patients, risks could not be evaluated in younger individuals.