CONTEXT: Although drug cues reliably activate the brain's reward system, studies rarely examine how the processing of drug stimuli compares with natural reinforcers or relates to clinical outcomes. OBJECTIVES: To determine hedonic responses to natural and drug reinforcers in long-term heroin users and to examine the utility of these responses in predicting future heroin use. DESIGN: Prospective design examining experiential, expressive, reflex modulation, and cortical/attentional responses to opiate-related and affective stimuli. The opiate-dependent group was reassessed a median of 6 months after testing to determine their level of heroin use during the intervening period. SETTING: Community drug and alcohol services and a clinical research facility. PARTICIPANTS: Thirty-three opiate-dependent individuals (mean age, 31.6 years) with stabilized opiate-substitution pharmacotherapy and 19 sex- and age-matched healthy non-drug users (mean age, 30 years). MAIN OUTCOME MEASURES: Self-ratings, facial electromyography, startle-elicited postauricular reflex, and event-related potentials combined with measures of heroin use at baseline and follow-up. RESULTS: Relative to the control group, the opiate-dependent group rated pleasant pictures as less arousing and showed increased corrugator activity, less postauricular potentiation, and decreased startle-elicited P300 attenuation while viewing pleasant pictures. The opiate-dependent group rated the drug-related pictures as more pleasant and arousing, and demonstrated greater startle-elicited P300 attenuation while viewing them. Although a startle-elicited P300 amplitude response to pleasant (relative to drug-related) pictures significantly predicted regular (at least weekly) heroin use at follow-up, subjective valence ratings of pleasant pictures remained the superior predictor of use after controlling for baseline craving and heroin use. CONCLUSIONS: Heroin users demonstrated reduced responsiveness to natural reinforcers across a range of psychophysiological measures. Subjective rating of pleasant pictures robustly predicted future heroin use. Our findings highlight the importance of targeting anhedonic symptoms within clinical treatment settings.