Objective To investigate the changes of serum levels of HMGB1 and sTLT-1 in patients with acute myocardial infarction (AMI) after percutaneous coronary intervention (PCI), and the impact on prognosis assessment. Methods A total of 241 cases of patients with AMI undergoing PCI treatment in our hospital were selected from March 2013 to June 2017. Clinical data were collected. The serum levels of HMGB1 and sTLT- 1 were detected by enzyme-linked immunosorbent assay (ELISA). All patients were follow-up after surgery. The incidence of major adverse cardiovascular events (MACE) during hospitalization and 12 months after discharge were recorded. Results Among 241 cases of patients, 63 (26.14%) cases of patients occurred MACE after PCI (MACE group), and 178 cases did not occur MACE (non-MACE group). The proportion of lesions involving the three vessels, the serum levels of HMGB1 and sTLT-1, and the Gensini score of patients in the MACE group were higher than in the non-MACE group (P < 0.05). The ROC curve analysis showed that, when the serum level of HMGB1 in predicting the occurrence of MACE, the serum level of HMGB1 was 64.73 pg/ml, the area under the curve was 0.868 (95% CI: 0.820, 0.916), the sensitivity was 87.3% (95% CI: 0.768, 0.937) and the specificity was 75.84% (95% CI: 0.698, 0.811); when the serum level of sTLT-1 in predicting the occurrence of MACE, the serum level of sTLT-1 was 620.84 pg/ml, the area under the curve was 0.753 (95% CI: 0.683, 0.823), the sensitivity was 81.0% (95% CI: 0.703, 0.886) and the specificity was 62.9% (95% CI: 0.570, 0.685); and when the two were combined, the area under the curve was 0.895 (95% CI: 0.849, 0.941), the sensitivity was 87.3% (95% CI: 0.768, 0.937), and the specificity was 79.8% (95% CI: 0.738, 0.848). Cox proportional hazard model analysis showed that TG [Rl^R = 1.629 (95% CI: 1.137, 2.334)], Gensini score [Rl^R = 1.052 (95% CI: 1.033, 1.070)], the serum levels of HMGB1 [Rl^R = 1.081 (95% CI: 1.049, 1.113)] and sTLT-1 [Rl^R = 1.008 (95% CI: 1.003, 1.013)] were the risk factors for MACE in patients with AMI after PCI treatment. Conclusions The occurrence of MACE in patients with AMI after PCI is related to serum levels of HMGB1 and sTLT-1, which are risk factors for prognosis of patients. They could be used as predictors of long-term prognosis of patients.