Use of prescription medication, alcohol, and illicit substances, and problems resulting from their use as well as depression and disability acceptance, were reported by 96 persons with long-term spinal cord injuries (SCI). Forty-three percent of the sample used prescription medications with misuse potential, and of these persons, 24% reported misusing one or more medications. Persons who used prescription medications were less accepting of their disability and were more depressed than persons who were not using prescription medications. Additionally, persons reporting problems resulting from prescription medication use were more depressed, and persons reporting problems resulting from nonprescription substance use were less accepting of their disability than were persons not reporting these problems. These results suggest that use of prescription and nonprescription substances by persons with SCI is associated with negative psychological outcomes.