Lactate clearance is affected by hepatic function. However, it is unclear whether the association between hepatic dysfunction and lactate clearance can act as a prognostic marker of clinical outcomes in patients with septic shock. We aimed to evaluate the association between lactate clearance and mortality in two cohorts of septic shock patient who had hepatic dysfunction based on their total serum bilirubin levels (TBIL). Lactate clearance at 24 h after the onset of septic shock was analyzed using two cohorts, sub-categorized into two groups based on TBIL: < 2 mg/dL and ≥ 2 mg/dL. In the derivation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while there was no significant difference in lactate clearance between non-survivors and survivors with TBIL < 2 mg/dL. Multivariate logistic regression analysis revealed that increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted odds ratio [OR]: 0.88, 95% confidence interval (CI): 0.80-0.97, P = 0.0075), Creatinine level ≥ 2 mg/dL group (adjusted OR: 0.88, 95% CI: 0.81-0.95, P = 0.00069) and APACHE II score ≥ 35 group (adjusted OR: 0.93, 95% CI: 0.87-0.98, P = 0.013). In the validation cohort, lactate clearance was lower in non-survivors than in survivors with TBIL ≥ 2 mg/dL, while no significant difference in lactate clearance was observed between non-survivors and survivors with TBIL < 2 mg/dL. Increased lactate clearance was significantly associated with decreased 28-day mortality in the TBIL ≥ 2 mg/dL group (10% lactate clearance, adjusted OR: 0.89, 95% CI: 0.83-0.96, P = 0.0038) and the association was just about significant in APACHE II score ≥ 35 group (adjusted OR: 0.86, 95% CI: 0.74-1.00, P = 0.051). In conclusion, increased lactate clearance in septic shock patients with hepatic dysfunction (TBIL ≥ 2 mg/dL) or high severity (APACHE II score ≥ 35) was associated with decreased 28-day mortality.