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Elevated circulating D-dimer levels have been shown to be a predictor of in-hospital mortality in a variety of diseases; however, the relationship between D-dimer and the in-hospital prognosis of non-ST-segment elevation myocardial infarction (NSTEMI) remains unclear. This retrospective study included 662 non-diabetic patients with NSTEMI. Independent risk factors were identified by multivariate analyses, and the receiver operating characteristic (ROC) curve analyses were performed to compare the predictive value of D-dimer, albumin (ALB), and D-dimer to albumin ratio (DAR) for in-hospital death in NSTEMI. Logistic regression model with restricted cubic spline (RCS) was used to further explore the linear or nonlinear relationship between D-dimer and the risk of death. In-hospital mortality occurred in 38 (5.7%) patients. Multivariate analysis showed that D-dimer (per increase of 500 ng) was identified as an independent predictor for in-hospital mortality in non-diabetic patients with NSTEMI (OR = 1.19, 95% CI: 1.03–1.40, P = 0.036). D-dimer demonstrated good predictive performance for in-hospital mortality with an area under the ROC curve (AUC) value of 0.75 (95% CI: 0.66–0.83), and there was no significant difference in the predictive ability of D-dimer, ALB (AUC = 0.70, 95% CI: 0.61–0.79) and DAR (AUC = 0.75, 95% CI: 0.66–0.84). In addition, RCS analysis showed a linear relationship between D-dimer and the risk of in-hospital mortality (P for nonlinear = 0.747). D-dimer can be used as a simple, reliable and valuable biomarker for predicting in-hospital mortality in non-diabetic patients with NSTEMI and is linearly associated with the risk of death.