Objectives. To characterize the effects of the onset of the COVID-19 pandemic on the risk environment of people who use drugs (PWUD) in Tijuana, Mexico. Methods. We used intensive participant-observation ethnography among street-based PWUD and key informants, such as frontline physicians and harm reductionists. Results. PWUD described an unprecedented cessation of police violence and extortion during the initial pandemic-related lockdown, though this quickly reversed and police violence worsened. Government-provided housing and medical treatment with methadone were temporarily provided to PWUD in a dedicated clinic, yet only for PWUD with COVID-19 symptoms. Concurrently, non‒COVID-19‒related hospital care became virtually inaccessible, and many PWUD died of untreated, chronic illnesses, such as hepatitis C, and soft-tissue infections. Border closures, decreases in social interaction, and reduced drug and sex tourism resulted in worsening food, income, and housing insecurity for many PWUD. By contrast, potent illicit drugs remained easily accessible in open-air drug markets. Conclusions. The pandemic exacerbated health risks for PWUD but also offered profound glimpses of beneficial structural changes. Efforts are needed in Tijuana and elsewhere to institutionalize positive pandemic-related shifts and ameliorate novel harms for PWUD. (Am J Public Health. 2022;112(S2):S199-S202. https://doi.org/10.2105/AJPH.2022.306796).