BACKGROUND: Only few studies had investigated the histopathological presentations of drug reaction with eosinophilia with systemic symptoms (DRESS). The results of these studies were diverse and not conclusive. A characteristic histopathological feature is still lacking. OBJECTIVE: We tempted to identify characteristic histopathological features in DRESS and to correlate them with clinical presentations. METHODS: We retrospectively collected data from patients treated from 1998 through 2015. Available skin specimens from probable or definite cases according to the RegiSCAR criteria were analysed for histopathological patterns, which were then compared with the patients' clinical presentations. Chi-squared test was used for comparisons, while Bonferroni correction was applied if multiple comparison tests were encountered. RESULTS: Fifty-six patients with an average age of 52 years were identified, including 22 definite cases. The single most common histopathological pattern was interface dermatitis (75%). The co-existence of two or more patterns in a skin specimen was common (62.5%). In such cases, the co-existence of three patterns (the eczematous pattern, the interface dermatitis pattern and the vascular damage pattern) was most frequently encountered. It exhibited a significantly higher likelihood of being definite cases (P = 0.004) and was significantly associated with high grades of cutaneous abnormalities (P < 0.001). It showed a trend towards having higher grades of haematological abnormalities in patients with co-existence of three patterns (P = 0.04). In addition, patients with the co-existence of three patterns tended to have a higher rate of reactivation of human herpesvirus-6 than those with other patterns but not statistically significant (P = 0.052). CONCLUSION: The co-existence of three histopathological patterns in a skin specimen is characteristic in DRESS and shows a significant association with clinical severity.