Objective To detect the expression of sphingosine 1-phosphate (S1P) in peripheral blood of patients with chronic heart failure (CHF), and explore the clinical predictive value of S1P and 6 MWD for the prognosis of CHF patients combined with 6-minute walk test distance (6MWD). Methods 165 patients with CHF from January 2022 to December 2022 were enrolled as CHF group, and 165 healthy subjects were selected as control group. Peripheral blood S1P was measured and 6MWD, LVEF was completed in all subjects. Person related was used to analyze the correlation between S1P expression, 6MWD and LVEF in peripheral blood of CHF patients. The clinical data, LVEF, 6MWD and S1P of peripheral blood were compared between the two groups of different prognosis. Logistics analysis was performed to analyze the influencing factors of the prognosis of CHF patients, and receiver operating characteristic curve (ROC) was used to evaluate the predictive value of 6MWD and S1P for the prognosis of CHF patients. Results The expression of S1P and 6MWD, LVEF in peripheral blood of CHF group were significantly lower than those of control group (P＜0.05). S1P expression in peripheral blood of CHF patients was positively correlated with LVEF (P＜0.05), and 6MWD was positively correlated with LVEF (P＜0.05). The proportion of coronary heart disease in CHF patients with good prognosis was significantly lower than that in patients with poor prognosis, and S1P, 6 MWD and LVEF were significantly higher than those in patients with poor prognosis (P＜0.05). Logistics regression analysis showed that S1P and 6 MWD were prognostic factors in CHF patients (P＜0.05). The area under the curve of S1P and 6 MWD for predicting the prognosis of CHF was 0.897 and 0.793, respectively, and the cutoff values were 0.459 and 0.634, respectively, corresponding to sensitivities of 68.6% and 79.3%, and specificities of 52.7% and 46.9%. The area under the curve of the combination of the two for predicting the prognosis of CHF was 0.941, and its sensitivity and specificity were 85.1% and 71.4%, respectively. Conclusion S1P combined with 6MWD can well predict the prognosis of CHF patients