OBJECTIVES The objective of this study was to assess the comparative effectiveness of clomethiazole against diazepam in the treatment of alcohol withdrawal syndrome (AWS) in the real-world. METHODS Following a retrospective design, this study is based on case report notes of patients consecutively treated for AWS at a University Clinic in Germany (Aachen), from 2008 to 2013. The primary outcomes were: scores of German version of the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar) in the first four days of therapy; duration of therapy; duration of hospital stay and rates of complications. Patients in the two groups (diazepam and clomethiazole) were matched for demographic factors and severity of withdrawal using propensity scores. RESULTS Seventy nine patients (Diazepam = 42; Clomethiazole = 37) were included. Mean age of patients (M = 69%, F = 30.4%) was 45±15 years. Duration of excessive alcohol use was 16 ± 12 years. On admission mean systolic and diastolic blood pressure was 139±20 and 88±13, respectively. Pulse rate was 100 ±18 per minute. CIWA-Ar scores at the end of each of the first four days of therapy were not statistically significantly different (ANOVA, p < 0.5) for the two therapies. Average duration of therapy was 3.81±2.9 days vs. 5.8 ±3.2 days (ANOVA - F = 8.6, p = 0.004), for clomethiazole and diazepam groups, respectively. Duration of hospital stay was 14.92±10.1 vs. 15±13 (ANOVA – F, p > 0.2), respectively. There was no difference in complication rates, except for seizures (higher in Diazepam group, Chi-square test, p = 0.023). CONCLUSIONS Clomethiazole and Diazepam seem to offer comparable effectiveness in resolving symptoms of AWS. Otherwise the notably shorter therapy duration and lower rates of complications for clomethiazole hints at some advantages such as faster recovery and lower costs of treatment, although this would have to be confirmed in future.