This review evaluates the impact of post-traumatic stress disorder (PTSD) and depression comorbidity on symptom severity within and across different populations. A sequential series of searches on PTSD and depression comorbidity was conducted using the MEDLINE and PsychINFO databases. Articles were considered for inclusion in the study if their abstract appeared to furnish sufficient information that suggested that symptom severity was modulated by PTSD and depression comorbidity when compared with those with only one disorder (PTSD or depression). After a careful review of 180 abstracts, 13 articles were selected for this review to provide up-to-date information on PTSD and depression comorbidity, and symptom severity. Overall, this review provides strong support for PTSD and depression comorbidity as a modulating factor for symptom severity across different populations.