We tested the hypothesis that a C-reactive protein and ferritin-based systemic inflammation contingency table can track mortality risk in pediatric severe sepsis. Prospective cohort study. Tertiary PICU. Children with 100 separate admission episodes of severe sepsis were enrolled. Blood samples were attained on day 2 of sepsis and bi-weekly for biomarker batch analysis. A 2 × 2 contingency table using C-reactive protein and ferritin thresholds was developed. A C-reactive protein of 4.08 mg/dL and a ferritin of 1,980 ng/mL were found to be optimal cutoffs for outcome prediction at first sampling (n = 100) using the Youden index. PICU mortality was increased in the "high-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL category (6/13 46.15%) compared with the "intermediate-risk" C-reactive protein greater than or equal to 4.08 mg/dL and ferritin less than 1,980 ng/mL or C-reactive protein less than 4.08 mg/dL and ferritin greater than or equal to 1,980 ng/mL categories (2/43 4.65%), and the "low-risk" C-reactive protein less than 4.08 mg/dL and ferritin less than 1,980 ng/mL category (0/44 0%) (odds ratio, 36.43 95% CI, 6.16-215.21). The high-risk category was also associated with the development of immunoparalysis (odds ratio, 4.47 95% CI, 1.34-14.96) and macrophage activation syndrome (odds ratio, 24.20 95% CI, 5.50-106.54). Sixty-three children underwent sequential blood sampling; those who were initially in the low-risk category (n = 24) and those who subsequently migrated (n = 19) to the low-risk category all survived, whereas those who remained in the "at-risk" categories had increased mortality (7/20 35%; p < 0.05). A C-reactive protein- and ferritin-based contingency table effectively assessed mortality risk. Reduction in systemic inflammation below a combined threshold C-reactive protein of 4.08 mg/dL and ferritin of 1,980 ng/mL appeared to be a desired response in children with severe sepsis.