Posttraumatic stress disorder (PTSD) commonly co-occurs with other psychiatric disorders. Data from epidemiologic surveys indicate that the vast majority of individuals with PTSD meet criteria for at least one other psychiatric disorder, and a substantial percentage have 3 or more other psychiatric diagnoses. A number of different hypothetical constructs have been posited to explain this high comorbidity; for example, the self-medication hypothesis has often been applied to understand the relationship between PTSD and substance use disorders. There is a substantial amount of symptom overlap between PTSD and a number of other psychiatric diagnoses, particularly major depressive disorder. It has been suggested that high rates of comorbidity may be simply an epiphenomenon of the diagnostic criteria used. In any case, this high degree of symptom overlap can contribute to diagnostic confusion and, in particular, to the underdiagnosis of PTSD when trauma histories are not specifically obtained. The most common comorbid diagnoses are depressive disorders, substance use disorders, and other anxiety disorders. The comorbidity of PTSD and depressive disorders is of particular interest. Across a number of studies, these are the disorders most likely to co-occur with PTSD. It is also clear that depressive disorder can be a common and independent sequela of exposure to trauma and having a previous depressive disorder is a risk factor for the development of PTSD once exposure to a trauma occurs. The comorbidity of PTSD with substance use disorders is complex because while a substance use disorder may often develop as an attempt to self-medicate the painful symptoms of PTSD, withdrawal states exaggerate these symptoms. Appropriate treatment of PTSD in substance abusers is a controversial issue because of the belief that addressing issues related to the trauma in early recovery can precipitate relapse. In conclusion, comorbidity in PTSD is the rule rather than the exception. This area warrants much further study since comorbid conditions may provide a rationale for the subtyping of individuals with PTSD to optimize treatment outcomes.