Patients with substance use (SUD) and posttraumatic stress disorders (PTSD) are at high risk for relapse. This study examined the reasons patients identify for their first substance use following discharge from SUD treatment. A total of 65 patients with and without PTSD completed clinical interviews, including an adapted version of the Relapse Interview [RI; Miller, W.R., & Marlatt, G.A. (1996). Appendix A: Relapse Interview. Addiction, 91(Suppl), 231–240.] at a 6-month follow-up. Qualitative data from the RI was consensus coded using Marlatt's taxonomy of relapse situations. Results indicated that patients with PTSD were less likely to report first substance use triggered by cue-based urges and more likely to report use in response to negative emotions of an interpersonal nature than those patients without PTSD. Other characteristics of first use associated with PTSD included greater subjective urges right before using, greater efforts to obtain substances and more likelihood to use to intoxication. Patients with unremitted PTSD reported poorer outcome and self-efficacy expectations than those without PTSD or with remitted PTSD. Implications for self-medication theory and clinical practice are discussed.