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Objectives Driven by an increasingly toxic drug supply, drug toxicity deaths in the United States and Canada have risen to unprecedented levels during the COVID-19 pandemic. This study aimed to characterize the prevalence of and the factors associated with a perceived decline in the quality of drugs during the COVID-19 pandemic among community-recruited cohorts of PWUD in Vancouver, Canada. Methods Data collection took place between July and November 2020. In adherence with COVID-19 safety protocols, questionnaires were administered by interviewers through remote means (e.g., phone or videoconference). Using multivariable logistic regression, we characterized the prevalence of and factors associated with a perceived decline in drug quality during the start of the COVID-19 pandemic in Vancouver, Canada. Results Of the 738 individuals included in this analysis, 272 (36.9%) reported that the quality of drugs declined during the COVID-19 pandemic. In multivariable analysis, perceived decline in the quality of drugs was significantly associated with: recent non-fatal overdose (adjusted odds ratio [AOR]=2.01, 95% Confidence Interval [CI]: 1.29–3.15), at least weekly injection drug use (AOR=1.94, 95% CI: 1.40–2.71), at least weekly crack use (AOR=1.61, 95%CI: 1.10–2.36), and at least weekly crystal methamphetamine use (AOR=1.46, 95%CI: 1.03–2.08). Discussion Over a third of PWUD perceived that the quality of drugs declined during the COVID-19 pandemic and these individuals were significantly more likely to report experiencing a recent non-fatal overdose, engaging in frequent injection drug and stimulant use. Study findings indicate the need for interventions to address the toxic drug supply, including providing a regulated supply.