Background Limited data are available on the clinical significance of lactate clearance (LC) in patients with cardiogenic shock (CS). This study investigated the prognostic role of LC in CS patients. Methods We analyzed data from 628 patients in the RESCUE registry, a multicenter, observational cohort enrolled between January 2014 and December 2018. Univariable logistic regression analysis was performed to determine the prognostic implications of 24 h LC, and then patients were divided into two groups according to the cut-off value of 24 h LC (high lactate clearance HLC group vs. low lactate clearance LLC group). The primary outcome was in-hospital mortality. We also assessed all-cause mortality at 12 month follow-up and compared the prognostic performance of 24 h LC according to initial serum lactate level. Results In the univariable logistic regression analysis, 24 h LC was associated with in-hospital mortality (odds ratio 0.989, 95% confidence interval CI 0.985-0.993, p < 0.001), and the cut-off value for the LC of the study population was 64%. The HLC group (initial 24 h LC greater than or equai to 64%, n = 333) had a significantly lower incidence of in-hospital death than the LLC group (n = 295) (25.5% in the HLC group vs. 42.7% in the LLC group, p < 0.001). During 12 months of follow-up, the cumulative incidence of all-cause death was significantly lower in the HLC group than in the LLC group (33.0% vs. 48.8%; hazard ratio 0.55; 95% CI 0.42-0.70; p < 0.001). In subgroup analysis, 24 h LC predicted in-hospital mortality better in patients with initial serum lactate > 5 mmol/L than in those with serum lactate less than or equai to 5 mmol/L (c-statistics of initial serum lactate > 5 mmol/L = 0.782 vs. c-statistics of initial serum lactate less than or equai to 5 mmol/L = 0.660, p = 0.011). Conclusions Higher LC during the early phase of CS was associated with reduced risk of in-hospital and 12 month all-cause mortalities. Patients with LC greater than or equai to 64% during the 24 h after CS onset could expect a favorable prognosis, especially those with an initial serum lactate > 5 mmol/L. Trial registration: RESCUE (REtrospective and prospective observational Study to investigate Clinical oUtcomes and Efficacy of left ventricular assist device for Korean patients with cardiogenic shock), NCT02985008, Registered December 5, 2016--retrospectively and prospectively registered, Keywords: Cardiogenic shock, Lactate clearance, Prognosis