The primary objective of the study was to describe non-relapse mortality (NRM) and the proportion of first events that are deaths in children with acute lymphoblastic leukemia (ALL). Secondary objectives were to identify groups at higher risk and to determine whether proportions have changed over time. We performed a systematic review of randomized pediatric ALL studies. From 1337 articles, 59 were included, comprising a total of 49 071 patients. The induction death rate was 1.38%, remission death rate was 1.94% and total NRM was 3.60%. Deaths were responsible for 53.84% of first events during induction and 13.03% in total. Standard risk patients had significantly lower NRM during remission. The year of study was not associated with NRM. The results of the study show that the rate of NRM in children with ALL is 3.60% and those with high risk ALL have significantly higher NRM during remission, but NRM has not changed over time. Future research should focus on the exploration of patient-related risk factors for NRM.