Objective:To investigate the therapeutic potential of therapeutic plasma exchange (TPE) combined with continuous venovenous hemofiltration (CVVH) in the treatment of children with severe sepsis and multiple organ dysfunction syndrome (MODS).Methods:It was a prospective randomized controlled study (RCT) involving 70 children with severe sepsis and MODS admitted to Anyang Maternal and Child Health Hospital from February 2019 to February 2023.According to random number table method, they were randomly divided into combination group (35 cases) and CVVH group (35 cases). Patients in the CVVH group were treated with CVVH alone, and those in the combination group were treated with TPE combined with CVVH.The antibiotic use time of the two groups was recorded and compared by the t test.The prothrombin time (PT), thrombin time (TT), partial prothrombin time (APTT), fibrinogen (FIB), and serum levels of interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), high mobility group protein B1 (HMGB1), Toll-like receptor 4 (TLR4) and soluble receptor (sFLT) levels before treatment and 48 h and 72 h after treatment were compared by the repeated measurement ANOVA for the overall comparison at multiple time points, and LSD- t test for pair-wise comparison.The 28-day survival of the two groups was recorded and compared by the Chi- square test. Results:The PT, TT and APTT at 48 h and 72 h after treatment were significantly lower in the combination group than those of CVVH group (all P<0.05). The FIB at 48 h[(2.15±0.42) g/L vs.(1.84±0.31) g/L]and 72 h after treatment [(2.89±0.27) g/L vs.(2.49±0.20) g/L]were significantly higher in the combination group than those of CVVH group (all P<0.05). The duration of antibiotic use in the combination group was significantly shorter than that of CVVH group [(11.33±1.16) d vs.(13.54±1.92) d, t=5.828, P<0.05]. Serum levels of IL-1β, IL-6 and TNF-α at 48 h and 72 h were significantly lower in the combination group than those of CVVH group (all P<0.05). Serum levels of HMGB1, TLR4 and sFLT at 48 h and 72 h were significantly lower in the combination group than those of CVVH group (all P<0.05). The 28-day survival of the combination group was significantly higher than that of CVVH group (94.29% vs.77.14%, χ2=4.200, P=0.040). Conclusions:TPE combined with CVVH can improve the coagulation function and inflammatory factor levels in children with severe sepsis and MODS, which may achieve therapeutic objectives by regulating the levels of HMGB1, TLR4 and sFLT, and improve the short-term prognosis.