The most common psychological and cognitive sequelae associated with deployments to Afghanistan (Operation Enduring Freedom) and Iraq (Operation Iraqi Freedom) are mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD). High rates of PTSD are often observed among Veterans with a history of mTBI, and persistent postconcussive symptoms commonly endorsed after mTBI are known to be associated with PTSD. Therefore, this study examined whether PTSD mediates relations between postconcussive symptoms and 2 indices of medical disease burden: 1) the number of disease categories positive for a diagnosis, or system disease burden, and 2) total number of physical diagnoses, or cumulative disease burden. Participants were 91 Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn Veterans seeking treatment at a Veterans Affairs Medical Center who screened positive for mTBI and later attended a follow-up Polytrauma clinic evaluation for neuropsychiatric assessment. Medical records were reviewed for a history of mTBI, postconcussive symptoms, and physician diagnoses, which were used to derive system and cumulative disease burden variables. Mediation was tested using bootstrapping procedures. Participants provided written informed consent and all study procedures were approved by both the VA and university institutional review boards. Postconcussive symptoms (r = 0.53) and PTSD symptoms (r = 0.32) were both associated with cumulative disease burden. Only postconcussive symptoms were associated with system disease burden (r = 0.32). Results of our follow-up mediation analysis suggest that PTSD did not mediate relations between postconcussive symptoms and cumulative disease burden (bootstrap coefficient = -0.02, 95% confidence interval [-0.05 to 0.01]). These findings join an emerging body of literature suggesting that postconcussive symptoms have a direct impact on Veterans' health above and beyond the effects of PTSD. Strengths of this study include the use of objective, clinician-diagnosed medical conditions as an indicator of health, whereas limitations include the use of self-report measures to assess postconcussive and PTSD symptoms. This study underscores the need for more original research on the impact of mTBI on the long-term health and readjustment of returning Veterans. Furthermore, this study highlights the need for additional research on the psychosocial and pathophysiological mechanisms underlying the link between mTBI and poor health.