Objectives: This study prospectively examined the independent courses of alcohol, drugs, and smoking over 18 months in 154 patients preparing for hepatitis C virus (HCV) treatment in relation to functioning, negative coping, and satisfaction with quality of life in data collected from a randomized controlled trial of multiple-family group psychoeducation for patients preparing for HCV treatment. Patients with HCV who had consistent abstinence, consistent use, or achievement of abstinence after study entry were examined for outcomes pertaining to functioning in the context of HCV, negative coping, and satisfaction with quality of life. Methods: Of 309 patients considering treatment for HCV recruited from outpatient clinics at two major university medical centers and a Veterans Affairs medical center for a randomized controlled trial of a psychoeducation intervention, 154 completed baseline, 6-month, and 18-month assessments. The assessments included structured diagnostic interviews; questionnaires examining functioning, coping, and satisfaction with quality of life; medical record review; and urine testing for substances of abuse. For these analyses, substance use patterns were determined as consistent abstinence, consistent use, and achieving abstinence after study entry for alcohol and drug use and smoking. Results: The entire sample generally improved in all of these three outcomes over the course of the study. The course of alcohol, drugs, and smoking predicted HCV-related functioning, negative coping, and satisfaction with quality-of-life outcomes over 18 months. Three specific patterns of use (consistent abstinence, consistent use, and achievement of abstinence after study entry) of these substances diverged in association with outcomes related to functioning, negative coping, and satisfaction with quality of life, not only across trajectories over time within substance types but also among types of substances. Conclusions: This study's finding that different substances were associated with distinct clinical outcomes suggests the need to conceptually unbundle different types of substances in managing HCV. Future research is needed to examine the clinical utility of further unbundling these substances and also to further investigate effects of various amounts of use of these substances.