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Although several studies have shown that use of angiotensin-converting enzyme inhibitors (ACEIs) potentially decreased amyotrophic lateral sclerosis (ALS) risk in animal models, to our knowledge, there has been no human study in the literature discussing this issue.To investigate the association between the use of ACEIs and the risk for developing ALS.This case-control study was conducted using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The case group comprised 729 patients with newly diagnosed ALS and a severely disabling disease certificate between January 1, 2002, and December 31, 2008. These cases were compared with 14 580 sex-, age-, residence-, and insurance premium–matched control individuals.Use of ACEIs was analyzed using a conditional logistic regression model that controlled for other antihypertensives, aspirin, steroids, nonsteroidal anti-inflammatory drugs, Charlson Comorbidity Index score, length of hospital stay, and number of outpatient visits. The cumulative defined daily dose (cDDD), which indicates the exposed duration of drug use, was estimated as the sum of dispensed DDD of drug and compared with the risk for ALS.All patients with ALS fulfilled El Escorial criteria in this study. Medical claim data past 1 to 5 years of ALS first diagnosis date for patients and claim data from their matched control individuals were included in the analysis.There was a dose-dependent inverse association between ACEI use and the risk for developing ALS. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 (95% CI, 0.65–1.07; P = .15) for the group prescribed ACEIs lower than 449.5 of the cDDD and 0.43 cDDD (95% CI, 0.26–0.72; P = .001) for the group with a cumulative ACEI use of greater than 449.5 cDDD. The association was most predominant in men older than 55 years.Use of ACEIs exhibited a dose-dependent inverse association with ALS. This study demonstrated a 57% risk reduction in the chance for developing ALS in people who used ACEIs greater than 449.5 cDDD in 4 years.