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M. M. Blessing (1); E. S. Yi (1); L. J. Langman (2); S. M. Jenkins (3); G. M. Spears (3); A. C. Roden. (1) (1) Divisions of Anatomic Pathology, (2) [...], Context: Recreational drug use is known to cause select histopathologic findings in the lungs. Systemic changes may also be seen in the lungs. There is a paucity of large cohort studies assessing histopathologic findings in the lungs of decedents who abused illicit drugs, prescription drugs, and/or alcohol. Design: We queried institutional autopsy files (1998-2014) for cases with a history of substance abuse (illicit, prescription, and/or alcohol) and/or positive postmortem toxicologic studies. We performed a retrospective review of histologic findings in lungs of these autopsy cases. Histologic findings of the interstitium, vasculature, airways, and pleura were recorded. Autopsy reports, and toxicology and clinical records were reviewed. Frequencies of drug categories and histology were compared by using Fisher exact tests. Results: Seventy-three autopsy cases (50 men with a median age of 45 years) were reviewed. Drug overdose/toxicity was the most common cause of death (53%) followed by blunt force trauma (10%). The most common histologic findings included pigmented macrophages (63%), smoking-related changes (56%), interstitial changes (40%), small airways changes (32%), and acute lung injury (22%). Associations included granulomas with fentanyl toxicity (P = .03) (predominantly nonnecrotizing), pigmented macrophages with positive urine THC result (P = .01), and marijuana abuse history (P = .01) (predominantly coarse, brown pigment), and with stimulant abuse history (P = .03) (generally "crunchy" brown pigment), and smoking-related changes with positive urine THC result (P = .02) and stimulant abuse history (P = .01). Conclusions: The identification of such histopathologic findings can help to identify previously unknown drug abuse and/or support a known clinical history of abuse in autopsy cases as well as in the surgical pathology setting.