Objective To investigate the significance of high mobility group box 1 (HMGB1) levels in polymyositis (PM) and dermatomyositis (DM) patients with interstitial lung disease and whether HMGB1 levels could predict disease outcome. Methods HMGB1 levels were measured in sera from 34 patients with PM/DM and from 34 healthy controls by ELISA. Results Significantly higher serum levels of HMGB1 were found in patients with PM [12.75 ng/ml (4.34-25.07 ng/ml), p < 0.001] and DM [20.75 ng/ml (3.80-124.88 ng/ml), p < 0.001] than in healthy controls [5.64 ng/ml (2.71-8.71 ng/ml)]. Importantly, the average HMGB1 level in PM/DM patients with interstitial lung disease (ILD) was 25.84 ng/ml, which is significantly higher than that in PM/DM patients without ILD [12.68 ng/ml] (p < 0.05). A receiver operating characteristic (ROC) curve analysis revealed that the serum HMGB1 cutoff value that best discriminated PM/DM patients with ILD from those without ILD was 14.5ng/ml. The area under the curve was 0.87 +/- 0.05, and the 95% Confidence interval (CI) was 0.77-0.98. The diagnostic sensitivity and specificity of this serum HMGB1 cutoff level was 84.6% and 89% respectively. Patients with higher levels of HMGB1 expression had lower overall survival rates and disease-free survival rates, whereas patients with lower levels of HMGB1 expression had higher survival rates. Conclusion Multivariate analysis showed that HMGB1 expression is a prognostic indicator for patient survival. These data support the notion that HMGB1 overexpression is involved in PM/DM progression for patients with ILD and is relative to its poor clinical outcomes.