Previous studies have shown an independent association between increased red cell distribution width (RDW) and mortality after acute myocardial infarction (AMI). However, evidence regarding the predictive significance of repeated measures of RDW in patients with AMI remains scarce. We aimed to investigate the association between the dynamic profile of RDW and in-hospital mortality in patients with AMI. This was a cross-sectional study. We extracted clinical data from the Medical Information Mart for Intensive Care IIIV1.4 database. Demographic data, vital signs, laboratory test data, and comorbidities were collected from the database. The clinical endpoint was in-hospital mortality. Cox proportional hazards models were used to evaluate the prognostic values of basic RDW, and the Kaplan–Meier method was used to plot survival curves. Subgroup analyses were performed to measure mortality across various subgroups. The repeated-measures data were compared using a generalized additive mixed model. In total, 3101eligible patients were included. In multivariate analysis, adjusted for age, sex, and ethnicity, RDW was a significant risk predictor of in-hospital mortality. Furthermore, after adjusting for more confounding factors, RDW remained a significant predictor of in-hospital mortality (tertile 3 vs tertile 1: hazard ratio 2.3; 95% confidence interval 1.39–4.01; P for trend <.05). The Kaplan–Meier curve for tertiles of RDW indicated that survival rates were highest when RDW was ≤13.2% and lowest when RDW was ≥14.2% after adjustment for age, sex, and ethnicity. During the intensive care unit stay, the RDW of nonsurvivors progressively increased until death occurred. Our findings showed that a higher RDW was associated with an increased risk of in-hospital mortality in patients with AMI.