Sepsis is a systemic, deleterious host response to infection leading to severe sepsis and septic shock. Thyroid dysfunction is associated with mortality in critically ill patients. We investigated the predictive value of thyroid hormone in comparison with CRP and IL-6. A total of 80 patients were included in a prospective, randomized, single center study in several critical care units of Cairo university hospitals. All were subjected to FT3, FT4, TSH, and CRP ratio measurements on admission and on fifth day. IL-6 was also measured on admission. Pan cultures were taken before antimicrobial treatment. APACHE II and SOFA scores were calculated. The days of mechanical ventilation, ICU length of stay as well as final outcome of survival, mortality rate were also calculated. FT3, FT4, TSH levels were within normal range on admission in 41 patients, 53 patients, 58 patients respectively. On the fifth day, FT3, FT4, TSH levels were below reference range in 61.3%, 31.2 %, and 23.8% of patients respectively. There was significant difference between the low levels of FT3 on admission and fifth day (p<0.001). By comparison of thyroid hormone levels in patients with sepsis, severe sepsis and septic shock; we found the mean level of FT3 was lower in patients with septic shock (1.3 ± 0.4 pg/ml) and severe sepsis (1.7 ± 0.2 pg/ml) as compared to patients with sepsis (2.4 ± 1.2 pg/ml). The mean FT3 level increased in survivors (2.9 ± 1.03 pg/ml) while it decreased in nonsurvivors (1.9 ± 0.89 pg/ml) (p<0.001).Mean CRP on fifth day was (19.1 ± 15.7 mg/l) in survivors and (162.2 ± 55 mg/l) in nonsurvivors (p<0.001). IL-6 levels showed high statistical significance between survivors (35.7 ± 34.7 pg/mL) and nonsurvivors (231.3 ± 178.4 pg/mL) (p<0.001). APACHE II and SOFA score showed statistical significance between both groups as well as duration of MV (p<0.005) and ICU stay (p<0.001).Correlation of FT3 on 5th day to CRP (r=-0.332, p=0.039), FT3 on 5th day to IL-6 (r=-0.339, p=0.035) in nonsurvivors. Correlation of FT3 on 5th day to APACHE II (r=-0.359, p=0.025) and SOFA score (r=-0.427, p=0.007). ROC curves indicated that FT3 on 5th day had the greatest power for predicting ICU mortality (AUC=0.855, sensitivity 87.2% & specificity 73.2%). CRP (AUC=0.984, sensitivity 100% and specificity 92.7%) is a better tool than IL-6 (AUC=0.934, sensitivity 92.3% and specificity 80.5%) in predicting mortality in sepsis. Thyroid dysfunction occurs during severe sepsis and septic shock. A decrease of FT3 levels during follow up may refer to adverse outcomes. FT3 levels were negatively correlated to CRP and IL-6 levels as well as APACHE II, SOFA scores. FT3 can be potentially used as a marker of disease severity and a predictor of mortality in patients with severe sepsis.