Pre-exposure prophylaxis (PrEP) is the use of medication to prevent disease in people who have not yet been exposed to the disease-causing agent. This often refers to the use of antiviral drugs for HIV prevention. Federal guidelines recommend the use of PrEP for HIV-negative adults who have higher-than-average risk of contracting HIV. Populations with serious mental illness are known to be at risk for HIV. Currently, the FDA has approved tenofovir/emtricitabine (Truvada) for PrEP. PrEP protects against HIV but not against other STDs or infections. It is highly effective for preventing HIV if used as prescribed, but much less effective when not taken consistently. There is little research on PrEP in patients with serious mental illness. When thinking about providing this evidence-based practice to patients with serious mental illness, there should be consideration of supports around education and adherence. PrEP should be prescribed by a clinician who is knowledgeable in its use, and consistent with the FDA label. Psychiatric medications are not currently listed among the known drug-drug interactions with PrEP.