Substance use (SU) disorders adversely impact health status and contribute to inappropriate health services use. This qualitative study sought to determine SU-related factors contributing to repeated hospitalizations and to identify opportunities for preventive interventions. Fifty Medicaid-insured inpatients identified by a validated statistical algorithm as being at high-risk for frequent hospitalizations were interviewed at an urban public hospital. Patient drug/alcohol history, experiences with medical, psychiatric and addiction treatment, and social factors contributing to readmission were evaluated. Three themes related to SU and frequent hospitalizations emerged: (a) barriers during hospitalization to planning long-term treatment and follow-up, (b) use of the hospital as a temporary solution to housing/family problems, and (c) unsuccessful SU aftercare following discharge. These data indicate that homelessness, brief lengths of stay complicating discharge planning, patient ambivalence regarding long-term treatment, and inadequate detox-to-rehab transfer resources compromise substance-using patients' likelihood of avoiding repeat hospitalization. Intervention targets included supportive housing, detox-to-rehab transportation, and postdischarge patient support.