OBJECTIVES: Study objectives were to examine (1) baseline differences in substance use motives (social, coping, enhancement, and physical discomfort) among older, middle-aged, and younger adults, and (2) whether age group moderated associations between substance use motives at baseline and substance use outcomes at six-month follow-up. DESIGN: Participants were assessed at baseline and followed for six months (91.1%). SETTING: U.S. military veterans receiving alcohol and/or opioid detoxification services. PARTICIPANTS: 298 participants in a study of telephone monitoring to improve detoxification outcomes. MEASUREMENTS: Baseline substance use motives were measured using the Motives for Alcohol and Drug Use questionnaire. At baseline and 6-month follow-up, substance use, substance use risk, and substance use protection were measured using the Brief Addiction Monitor. RESULTS: One-way analyses of variance with post-hoc tests found that older adults endorsed significantly lower social and coping motives for substance use than younger and middle-aged adults, and significantly lower enhancement motives than younger adults. Moderation models were analyzed using linear regression, with demographics controlled. Significant interactions of motives with age group revealed that higher endorsement of enhancement motives for substance use was associated with less protection against substance use among older adults but not among younger or middle-aged adults. CONCLUSIONS: Enhancement motives among older adults may represent a specific age-related risk for substance use. Older adults who use substances to enhance their mood and well-being may need additional resources and skills for improving mental health so that unhealthy substance use is reduced or avoided.