RATIONALE: Identifying the predictors of relapse in detoxified alcohol-dependent patients is crucial for effective surveillance procedures and the optimization of treatment. Physiological measures such as functional MRI activity and heart rate variability have been shown as potential markers of relapse prediction. OBJECTIVES: Our aim was to assess differential pupillary reactions to alcohol-related cues as an objective physiological candidate predictor of relapse. METHODS: We examined the relationship between cue-elicited pupillary reactions to alcohol stimuli and luminance-controlled neutral stimuli in 21 detoxified alcohol-dependent patients and subsequent relapse outcome at a 4-month follow-up. RESULTS: Differential pupillary dilation to alcohol stimuli as compared to neutral stimuli at 150 to 250 ms after stimulus onset substantially improved the model prediction of relapse outcome (additional 27% of variance) beyond that achieved from five standardized questionnaires on alcohol craving, alcohol use, problematic use severity, depressive tendencies, and duration of abstinence (47% of variance). In contrast, alcohol craving did not improve relapse model prediction. CONCLUSIONS: This pilot study shows that alcohol-dependent patients with greater pupillary dilation to alcohol stimuli are more vulnerable to relapse, and that pupillometry presents as an important tool for addiction science.