Whether lactate clearance (LC) influences outcomes differently depending on the infection site in sepsis cases is not fully elucidated. Herein, we analyzed LC's clinical utility as a predictor of patient outcomes according to infection site. This retrospective study, conducted at two tertiary emergency critical care medical centers in Japan, included patients with sepsis or septic shock. The associations between infection site (lungs vs. other organs) and in-hospital mortality and ventilator-free days (VFDs) were evaluated using univariable and multivariate analyses. We assessed LC's ability to predict in-hospital mortality using the area under the receiver operating characteristic curve. Among 369 patients with sepsis, infection sites were as follows: lungs, 186 (50.4%); urinary tract, 45 (12.2%); abdomen, 102 (27.6%); and other, 36 (9.8%). Patients were divided into a pneumonia group or non-pneumonia group depending on their infection site. The pneumonia group displayed a higher in-hospital mortality than the non-pneumonia group (24.2% vs. 15.8%, p = 0.051). In the multivariate analysis, lower LC was associated with higher in-hospital mortality adjusted odds ratio (AOR), 0.97; 95% confidence interval (CI) 0.96-0.98; p < 0.001 and fewer VFD adjusted difference p value (AD), - 1.23; 95% CI - 2.42 to - 0.09; p = 0.025 in the non-pneumonia group. Conversely, LC did not affect in-hospital mortality (AOR 0.99; 95% CI 0.99-1.00; p = 0.134) and VFD (AD - 0.08; 95% CI - 2.06 to 1.91; p = 0.854) in the pneumonia group. Given the differences in the impact of LC on outcomes between the pneumonia and non-pneumonia groups, this study suggests that optimal treatment strategies might improve outcomes. Further studies are warranted to validate our results and develop optimal therapeutic strategies for sepsis patients.