A paucity of information regarding mental health exists for patients presenting for HIV non occupational post-exposure prophylaxis (nPEP). We reviewed electronic medical records of 894 adult nPEP patients seen at a large Boston community health center between 1997 and 2013. Of 821 patients with consensual sexual exposures, 88.3% were men who have sex with men, and 40.0% had a mental health diagnosis. Diagnoses included: depression (24.4%), anxiety (21.9%), attention deficit disorder (7.8%), post-traumatic stress disorder (3.3%), and psychotic disorders (3.3%). Of 129 patients with substance use disorders, alcohol dependence (65.9%) and crystal methamphetamine (43.4%) predominated. Unprotected receptive anal intercourse was associated with psychotic disorders (aOR=4.86;95%CI:1.76–13.5) and substance use disorders (aOR=1.89;95%CI:1.28–2.80). Substance use at the time of exposure was associated with: depression (aOR=1.95;95%CI:1.36–2.80), anxiety (aOR=2.22;95%CI:1.51–3.25), attention deficit disorder (aOR=1.96;95%CI:1.18–3.27), and substance use disorder (aOR=4.78;95%CI:3.30–6.93). Mental illness should be screened for and addressed at nPEP visits to optimize HIV risk-reduction.