Objective To study the dynamic changes in plasma D-dimer and its prognostic value in children with severe hand-foot-mouth disease (HFMD). Methods A total of 95 children who suffered from HFMD between May 2010 and September 2012, including 65 cases of severe HFMD (observation group) and 30 cases of non-severe HFMD (control group), were enrolled in the study. Plasma D-dimer levels of the observation group on days 1, 2, 3, 4 and 5 were compared with plasma D-dimer levels of the control group on day 1 after admission. In the observation group, plasma D-dimer levels on days 1, 2, 3, 4 and 5 were compared. The prognostic value of plasma D-dimer was analyzed using the receiver operating characteristic (ROC) curve. Results Of the 65 cases in the observation group, 15 died, and 50 survived. All the 30 cases in the control group survived. Plasma D-dimer levels in the observation group on days 1, 2, 3, 4 and 5 were significantly higher than in the control group on day 1 after admission (P<0.05). In the observation group, there were significant differences between plasma D-dimer levels on days 1, 2, 3, 4 and 5 (P<0.01), and plasma D-dimer level was the highest on day 1 after admission and second highest on the next day. Of the patients in the observation group, those who died had significantly higher plasma D-dimer levels on day 1 after admission than those who survived (P<0.05). In the observation group, plasma D-dimer levels on day 1 after onset had an area under the ROC curve of 0.877 (95% confidence interval: 0.785-0.969) and an optimal cut-off value of 582.10 μg/L (80% sensitivity and 78% specificity) for predicting mortality. Conclusions Children with severe HFMD have significantly increased plasma D-dimer levels, and the severer the condition, the higher the value. Plasma D-dimer levels can be used as one of the important indices for assessing the severity and prognosis of severe HFMD.