Objective To explore the risk factors affecting the prognosis of young and middle-aged patients with cerebral infarction, and establish a clinical prognostic prediction model for its prognosis and individualized treatment. Methods A total of 294 young and middle-aged patients with cerebral infarction hospitalized in Wusong Branch of Zhongshan Hospital, Fudan University from Jan. 1, 2018 to Jan. 1, 2020 were included. The baseline data such as age, gender, past history, National Institutes of Health stroke scale (NIHSS) score and blood indexes were collected. The gene polymorphisms of ring finger protein 213 (RNF213) gene (rs112735431), histone deacetylase 9 (HDAC9) gene (rs2107595, rs2240419, rs2389995) and methylenetetrahydrofolate reductase (MTHFR) gene (C677T) were detected. According to the clinical outcomes at 1-year follow-up, 294 patients were divided into non-progression group (177 cases, 60.20%) and progression group (117 cases, 39.80%). The above indexes were compared between the 2 groups. The patients were divided into training set and test set by a ratio of 7:3. With the above indexes as independent variables and the clinical outcome at 1-year follow-up as dependent variable, the data of the training set were used for logistic regression analysis to identify the risk factors of prognosis and to establish a prognostic prediction model. The data of the training set and test set were used for receiver operating characteristic (ROC) curve analysis to evaluate the value of the model. Results The NIHSS score and levels of serum creatinine, total bilirubin and homocysteine in the progression group were significantly higher than those in the non-progression group (all P<0.05); and the distribution of MTHFR (C677T) gene polymorphism was different between the 2 groups (P<0.01). Logistic regression analysis showed that the risk of disease progression increased by 76.8% with every 1 point increment of NIHSS score (odds ratio[OR]=1.768, 95% confidence interval[CI] 1.479-2.112); the risk of disease progression in patients with TT genotype of MTHFR (C677T) gene was 4.128 times higher than that in patients with CC genotype (OR=4.128, 95% CI 1.497-11.383); and the risk of disease progression in patients with hypertension was 3.421 times higher than that in patients without hypertension (OR=3.421, 95% CI 1.353-8.645). The area under curve (AUC) of ROC curve in the training set was 0.856 (95% CI 0.806-0.906), and that in the test set was 0.847 (95% CI 0.756-0.937), indicating good prediction ability of the model. Conclusion NIHSS score, MTHFR (C677T) gene polymorphism and hypertension are risk factors for the progression of cerebral infarction in young and middle-aged patients. The clinical prognostic model based on NIHSS score, MTHFR (C677T) gene polymorphism and hypertension is helpful in evaluating prognosis of young and middle-aged patients with cerebral infarction.