Background: The objective of this retrospective study was to compare the effectivity and tolerability of diazepam and clomethiazole in the treatment of alcohol withdrawal syndrome (AWS) in a large clinical sample. Methods: The data of 566 patients admitted to an intensive care psychiatric unit in Germany (2010-2014) were evaluated. The course of withdrawal was analyzed on a matched sample (n = 152) consisting of a diazepam group (n = 76) and a clomethiazole group (n = 76). Medical assessment was based on a standardized point-based symptom rating scale called AESB (Alkoholentzugssymptom-Bogen), a German modified version of the Revised Clinical Institute Withdrawal Assessment of Alcohol Scale (CIWA-Ar). Results: Although the mean daily symptom reduction did not differ significantly, patients treated with clomethiazole were treated significantly shorter and needed less concomitant antipsychotic medication. Numbers of complications and adverse events did not show significant differences. Conclusion: Both clomethiazole and diazepam were effective and equally safe in the treatment of AWS. Clomethiazole provided a faster withdrawal and required less concomitant antipsychotic medication and therefore might be the more favorable option for patients and physicians. Taken into account the methodological limitations of the study (retrospective design, secondary matching, missing randomization, use of clomethiazole as drug of first choice), further studies are needed to confirm this result.