Objectives. To explore the implementation and effectiveness of the British Columbia, Canada, risk mitigation guidelines among people who use drugs, focusing on how experiences with the illicit drug supply shaped motivations to seek prescription alternatives and the subsequent impacts on overdose vulnerability.

Methods. From February to July 2021, we conducted qualitative interviews with 40 people who use drugs in British Columbia, Canada, and who accessed prescription opioids or stimulants under the risk mitigation guidelines.

Results. COVID-19 disrupted British Columbia’s illicit drug market. Concerns about overdose because of drug supply changes, and deepening socioeconomic marginalization, motivated participants to access no-cost prescription alternatives. Reliable access to prescription alternatives addressed overdose vulnerability by reducing engagement with the illicit drug market while allowing greater agency over drug use. Because prescriptions were primarily intended to manage withdrawal, participants supplemented with illicit drugs to experience enjoyment and manage pain.

Conclusions. Providing prescription alternatives to illicit drugs is a critical harm reduction approach that reduces exposure to an increasingly toxic drug supply, yet further optimizations are needed. (Am J Public Health. 2022;112(S2):S151–S158. https://doi.org/10.2105/AJPH.2021.306692)