This study assessed the relationship of non-injected illicit drug use and infectious disease seropositivity for human immunodeficiency virus (HIV-1), hepatitis B virus (HBV), hepatitis C virus (HCV), and Syphilis. In a retrospective review of 986 donor charts recovered from 2009 to 2011 at a single tissue bank, the absence of reported non-injected illicit drug use corresponded with seropositivity in 6.61%, of recovered donors while reported illicit drug use in the medical and social history corresponded with seropositivity in 11.25%, representing a 70% increased risk. There was no significant difference noted for overall seropositivity rates between types on noninjected illicit drugs, although donors that used cocaine had a higher incidence of HIV, while marijuana use was associated with a higher rate of HBV, HCV, and syphilis positivity. Toxicology screening results were not an accurate predictor of seropositivity (PPV=3.77%; NPV=91.56%). Further, the degree of relationship between the donor and the next of kin had no bearing on the veracity of actual drug use when comparing the response of the medical-social history and the toxicology screen.