Evidence suggests that posttraumatic stress disorder (PTSD) and substance use disorders (SUD) are associated with poorer physical health among U.S. veterans who served in Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF). No research of which we are aware has examined the independent and interactive effects of PTSD and SUD on medical comorbidity among OEF/OIF veterans. This cross-sectional study examined medical record data of female and male OEF/OIF veterans with ≥ 2 Veterans Affairs primary care visits (N = 73,720). Gender-stratified logistic regression analyses, adjusted for sociodemographic factors, were used to examine the association of PTSD, SUD, and their interaction on the odds of medical diagnoses. PTSD was associated with increased odds of medical diagnoses in 9 of the 11 medical categories among both women and men, range of odds ratios (ORs) ranged from 1.07 to 2.29. Substance use disorders were associated with increased odds of 2 of the 11 medical categories among women and 3 of the 11 medical categories among men; ORs ranged from 1.20 to 1.74. No significant interactions between PTSD and SUD were detected for women or men. Overall, findings suggest that PTSD had a stronger association with medical comorbidity (in total and across various medical condition categories) than SUD among female and male OEF/OIF veterans.