Objectives: Multiple organ dysfunction syndrome (MODS) with secondary hemophagocytic lymphohistiocytosis (SHLH) causes significant mortality, while continuous renal replacement therapy (CRRT) is commonly conducted. The objective is to identify the predictor factors associated with poor outcomes in pediatric patients with SHLH-associated MODS who received CRRT. Design: A multicenter prospective nested case-control study. Setting: In four PICUs of tertiary university children’s hospital in Shanghai from September 2013 to August 2018. Patients: Pediatric patients receiving CRRT due to SHLH-associated MODS from September 2013 to August 2018. Interventions: None. Measurements and Main Results: Overall PICU mortality rate was 46.15% (24/52). Less respiratory (28.6% vs. 87.5%, P<0.001) or cardiovascular dysfunction (25.0% vs. 83.3%, P<0.001) caused in survivors at CRRT initiation, as well as reduced demands of mechanical ventilation and vasoactive agents (28.6% vs. 87.5%,17.9 % vs. 66.7 %, both P<0.001). Non-survivors had higher levels of serum LDH (1404.5 (713.25, 2793) vs. 982.7 (692, 1461) (U/L), P = 0.037), lactic acid (1.9 (1.3, 4.53) (mmol/L) vs. 1.65 (0.8, 2.45) , P=0.034), triglyceride (2.88 (1.94, 5.08) (mmol/L) vs. 2.41 (1.63, 3.32), P=0.032) and IL-6 (28.66 (17.77, 113.63) (pg/ml) vs.0.98 (0.1, 4.63) P=0.000). More than 3 organ dysfunction (Odd ratio [OR] : 3.464; 95% confidence interval [CI] [1.018-11.788], P = 0.047), and the serum IL-6 level higher than 13.12 pg/mL (OR:1.388; 95% CI [1.058-1.821], P = 0.018 ) were two independent risk factors for mortality. Conclusions: The number of organ dysfunction and IL-6 levels at CRRT initiation are the independent risk factors for mortality in SHLH-associated MODS patients.