In patients with sepsis, outcome prediction plays an important role in influencing therapeutic decision making. In this nationwide, prospective, observational cohort study of sepsis patients conducted between September 2019 and December 2020, we evaluated a novel scoring system using serial Sequential Organ Failure Assessment (SOFA) scores and serum lactate to accurately predict mortality in sepsis. Based on the serum lactate score (Lac-score), patients were assigned to 5 categories: lactate < 2, ≥ 2 to < 4, ≥ 4 to < 8, ≥ 8 to < 12, and ≥ 12 mmol/L. Lac-SOFA score was defined as the sum of Lac-score and SOFA score. After screening 7113 patients, 379 were excluded and 6734 were included in analysis. In-hospital mortality AUROC for serial Lac-SOFA score from initial to ICU day 3 was significantly higher than that for serial SOFA score (initial, 0.679 vs. 0.656, day 1, 0.723 vs. 0.709, day 2, 0.760 vs. 0.747, and day 3, 0.797 vs. 0.781; DeLong's test, p < 0.001). The initial Lac-SOFA score significantly correlated with in-hospital mortality when the patients were divided into five classes based on 5-point intervals (p < 0.05). Serial evaluation of lactate levels with the SOFA score may improve the predictive accuracy of the SOFA score for determining mortality risk in sepsis patients.