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Co-occurrence of lower respiratory symptoms (LRS) and posttraumatic stress disorder (PTSD) has been increasingly recognized among responders and survivors of the World Trade Center (WTC) disaster. Information is limited on the degree which comorbidity intensifies symptoms and compromises quality of life across exposed groups.Among responders who completed the first and second Registry surveys, measures of respiratory illness, psychological distress, and diminished quality of life were compared between responders comorbid for LRS and PTSD and responders with only LRS or PTSD.Of 14,388 responders, 40% of those with LRS and 57% of those with PTSD were comorbid. When demographic and WTC exposure-related factors were controlled, comorbid responders compared to those with LRS alone were twice as likely to have frequent dyspnea and to have sought care for dyspnea. Compared to responders with PTSD alone, comorbid responders were 2.1 times more likely to report intense re-experiencing of the disaster, 2.5 times more likely to express feelings of significant non-specific psychological distress, and 1.4 times more likely to have received mental health care. Comorbid responders were approximately three times more likely to report only fair or poor general health and more than twice as likely to report being unable to perform usual activities for ≥14 of 30 days before interview.Outcomes in comorbid responders were similar to or more severe than in comorbid survivors. Health care and disaster relief providers must suspect comorbid illness when evaluating responders' respiratory or mental illnesses and consider treatment for both. Am. J. Ind. Med. 56:1251–1261, 2013. © 2013 Wiley Periodicals, Inc.