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The authors recruited 99 injection drug users to assess the psychometric properties of a new self-report questionnaire—the Harm Reduction Self-Efficacy Questionnaire (HRSEQ)—designed to measure injection drug users' confidence to employ 15 specific health-preserving coping skills in different types of high-risk situations (experiencing withdrawal, feeling depressed, and feeling social pressure to use drugs unsafely). Scores for each high-risk situation had good internal consistency (αs = .89–.92) and good 1-week test–retest reliability (rs = .70–.85). Comparison with measures of drug-related problems, use of coping skills, and health self-efficacy supported both construct and discriminant validity of the HRSEQ. Exploratory factor analyses revealed 3 major themes (cleanliness precautions, overdose precautions, and safer injection practices) that summarized most, but not all, of the 15 items. Mean differences among the 3 situations suggest that harm reduction self-efficacy should be assessed in the context of specific high-risk situations.