This study evaluated psychiatric symptoms preceding and following initial posttreatment substance use episodes. 125 veterans meeting DSM-IV criteria for alcohol, cannabis, and/or stimulant dependence at treatment entry were followed with quarterly interviews for one year. Approximately half of the sample met criteria for substance use disorders only (n = 65; SUD-only) and half additionally met criteria for an independent non-substance related Axis I disorder (n = 60; SUD-PSY). SUD-PSY adults reported more psychiatric symptoms preceding and following substance use compared to SUD-only adults. Depression and anxiety symptoms were commonly reported by both groups. Symptoms typically did not change or worsened after substance use, with depression worsening more than anxiety or psychotic symptoms. Findings are discussed in relation to the Self-Medication Hypothesis and the Rebound Hypothesis.