Abstract: The presentation of comorbid post-traumatic stress disorder (PTSD) and substance use disorder (SUD) differs by substance type. The current study applied network analysis to explore the relationships between diagnostic symptom clusters by examining the strength and direction of unique associations between PTSD and SUD. Network analyses were estimated using a sample of 422 veterans diagnosed with co-occurring PTSD/SUD initiating psychotherapy for PTSD while receiving concurrent outpatient SUD treatment as part of a randomized clinical trial. Separate network models were estimated for PTSD and the three most common SUD in the sample: alcohol use disorder (AUD), cannabis use disorder (CUD) and stimulant use disorder (StUD). Trauma-related intrusions and alcohol-related social impairment were the bridging symptom clusters that connected PTSD and AUD. Symptom clusters that connected PTSD and CUD were trauma-related intrusions and hyperarousal symptoms. Trauma-related alterations in cognition and mood and stimulant-related pharmacological symptoms were the bridging symptom clusters that connected PTSD and StUD. Each network of symptom clusters culminated in the trauma-related avoidance cluster, suggesting avoidance may represent a final outcome of the downstream effects of these symptoms. Across models, PTSD and SUD symptom clusters both served as sources of activation driving the comorbidity. There were also few and relatively weak bridging symptom clusters that connected PTSD/SUD, suggesting symptom change in one disorder may have minimal effect on the other disorder. Therefore, simultaneously treating PTSD and SUD as well as employing individualized treatment planning to target prominent symptoms may be most beneficial for veterans with PTSD/SUD.