ObjectiveTo evaluate  the efficacy of ganglioside on treatment of severe handfootmouth disease (HFMD) in children, and effect on serum neuronspecific enolase (NSE) as well as plasma S100 β protein levels.MethodsOne hundred and forty cases of severe HFMD patients in a hospital from April 2011 to June 2014 were  randomly divided into routine therapy group and trial group, and 30 healthy children who received physical examination in outpatient department during the same period were selected as control.  Children in routine therapy group were given antiviral and intracranial decompression therapy; trial group were administered ganglioside in addition to routine therapy , levels of NSE and S100 β protein levels of 3 groups, as well as clinical efficacy between  routine therapy group and trial group were compared. ResultsTotal efficacy rate of trial group was significantly higher than routine therapy group ( 91.43%［64/70］ vs  78.57%［55/70］，χ2=4.54，P＜0.05). The levels of NSE and S100 β protein in children with severe HFMD were significantly higher than control group (［17.63±4.21）μg/L vs ［8.79±2.12］μg/L; ［492.05±119.33］ng/L vs ［296.35±91.02］ng/L，both P＜0.01) . NSE and S100 β protein levels of routine therapy group and trial group before treatment were not significantly different(both P>0.05); after 10day treatment, NSE and S100 β protein levels of both groups were lower than before treatment (both P＜0.01),  the decreasing level of NSE and S100 β protein in trial group were both higher than routine therapy group（［10.18±2.36］ μg/L vs ［5.87±3.03］μg/L; ［247.55±64.64］ng/L vs ［113.97±43.44］ng/L ) (both P＜0.01). ConclusionGanglioside has obvious therapeutic efficacy on severe HFMD in children, and can effectively reduce brain damage markers NSE and S100 β protein.