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The optimal resuscitation strategy for patients with severe sepsis in resource-limited settings is unknown. Therefore, we determined the association between intravenous fluids, changes in vital signs and lactate after the first 6 hours of resuscitation from severe sepsis, and in-hospital mortality at a hospital in Uganda.We enrolled patients admitted with severe sepsis to Mbarara Regional Referral Hospital and obtained vital signs and point-of-care blood lactate concentration at admission and after 6 hours of resuscitation. We used logistic regression to determine predictors of in-hospital mortality.We enrolled 218 patients and had 6 hour postresuscitation data for 202 patients. The median (interquartile range) age was 35 (26–50) years, 49% of patients were female, and 57% were HIV infected. The in-hospital mortality was 32% and was associated with admission Glasgow Coma Score (adjusted odds ratio [aOR], 0.749; 95% confidence interval [CI], 0.642–0.875; P < .001), mid-upper arm circumference (aOR, 0.876; 95% CI, 0.797–0.964; P = .007), and 6-hour systolic blood pressure (aOR, 0.979; 95% CI, 0.963–0.995; P = .009) but not lactate clearance of 10% or greater (aOR, 1.2; 95% CI, 0.46–3.10; P = .73).In patients with severe sepsis in Uganda, obtundation and wasting were more closely associated with in-hospital mortality than lactate clearance of 10% or greater.