No study has directly measured tissue lactate clearance in patients with sepsis during the post-resuscitation period. In this study we aimed to assess in ICU patients with sepsis (n = 32) or septic shock (n = 79)—during the post-resuscitation phase—the relative kinetics of blood/tissue lactate clearances and to examine whether these are associated with outcome. We measured serially—over a 48-h period—blood and adipose tissue interstitial fluid lactate levels (with microdialysis) and we calculated lactate clearance. Statistics included mixed model analysis, Friedman’s analysis of variance, Wilcoxon’s test, Mann-Whitney’s test, receiver operating characteristics curves and logistic regression. Forty patients died (28-day mortality rate = 28%). Tissue lactate clearance was higher compared to blood lactate clearance at 0–8, 0–12, 0–16, 0–20 and 0–24 h (all p < 0.05). Tissue lactate clearance was higher in survivors compared to non-survivors at 0–12, 0–20 and 0–24 h (all p = 0.02). APACHE II along with tissue lactate clearance <30% at 0–12, 0–20 and 0–24 h were independent outcome predictors. We did not find blood lactate clearance to be related to survival. Thus, in critically ill septic patients, elevated tissue (but not blood) lactate clearance, was associated with a favorable clinical outcome.