This document provides revised guidance for the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) on comprehensive HIV prevention for people who inject drugs. It endorses a package of three core interventions: community-based outreach programs, sterile needle and syringe programs, and drug dependence treatment including medication-assisted treatment. The guidance outlines evidence that these interventions can significantly reduce risky drug use behaviors and HIV transmission when implemented together in a comprehensive manner.