Background and aims <p>The prognostic relevance of Remnant cholesterol (RC) in acute myocardial infarction (AMI), particularly in diabetes mellitus (DM) patients, remains unclarified. This research aimed to explore the interaction between elevated RC and DM on the prognosis of AMI, with the goal of improving risk stratification and guiding intervention strategies.</p> Methods <p>In this retrospective, single-center study, 520 AMI patients were recruited. Basic and follow-up information was acquired, with the primary endpoint being major adverse cardiovascular events (MACE) and the secondary endpoint being cardiac mortality. Multiplicative and additive interactions were assessed to determine the combined impact of RC and DM on prognosis. Analytical methods included Cox regression, Kaplan–Meier survival, and ROC analyses.</p> Results <p>Over a median follow-up of 45 (42–49) months, 120 (23.08%) MACEs and 35 (6.73%) cardiac mortalities were observed. An additive interaction between elevated RC and DM was positively related to MACEs, with the attributable proportion suggesting that 62% of MACE risk could be attributed to this interaction. The synergy index was 3.46 for MACE, suggesting that the combined risk of both factors exceeded the sum of their individual risks. Multivariate Cox regression analysis identified RC as a significant predictor of both MACEs and cardiac death. Kaplan–Meier survival curves indicated an obvious increase in MACE when both high RC and DM were present (log-rank test, <i>P</i> &lt; 0.001). ROC analysis demonstrated that AUC for RC in estimating MACEs was higher in DM patients, reaching 0.676 (95% CI 0.567–0.786).</p> Conclusions <p>The combined presence of elevated RC and DM exerts a synergistic effect, providing valuable insights for the risk stratification of AMI patients.</p>