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: Introduction: People living with HIV (PLWH) and/or who inject drugs may experience lower vaccine effectiveness (VE) against SARS‐CoV‐2 infection. Methods: A validated algorithm was applied to population‐based, linked administrative datasets in the British Columbia COVID‐19 Cohort (BCC19C) to ascertain HIV status and create a population of PLWH and matched HIV‐negative individuals. The study population was limited to individuals who received an RT‐PCR laboratory test for SARS‐CoV‐2 between 15 December 2020 and 21 November 2021 in BC, Canada. Any history of injection drug use (IDU) was ascertained using a validated administrative algorithm. We used a test‐negative study design (modified case−control analysis) and multivariable logistic regression to estimate adjusted VE by HIV status and history of IDU. Results: Our analysis included 2700 PLWH and a matched population of 375,043 HIV‐negative individuals, among whom there were 351 and 103,049 SARS‐CoV‐2 cases, respectively. The proportion of people with IDU history was much higher among PLWH compared to HIV‐negative individuals (40.7% vs. 4.3%). Overall VE during the first 6 months after second dose was lower among PLWH with IDU history (65.8%, 95% CI = 43.5–79.3) than PLWH with no IDU history (80.3%, 95% CI = 62.7–89.6), and VE was particularly low at 4–6 months (42.4%, 95% CI = −17.8 to 71.8 with IDU history vs. 64.0%; 95% CI = 15.7–84.7 without), although confidence intervals were wide. In contrast, overall VE was 88.6% (95% CI = 88.2–89.0) in the matched HIV‐negative population with no history of IDU and remained relatively high at 4–6 months after second dose (84.6%, 95% CI = 83.8–85.4). Despite different patterns of vaccine protection by HIV status and IDU history, peak estimates were similar (≥88%) across all populations. Conclusions: PLWH with a history of IDU may experience lower VE against COVID‐19 infection, although findings were limited by a small sample size. The lower VE at 4–6 months may have implications for booster dose prioritization for PLWH and people who inject drugs. The immunocompromising effect of HIV, substance use and/or co‐occurring comorbidities may partly explain these findings., INTRODUCTION People living with HIV (PLWH) and people who inject drugs (PWID) are two populations that often overlap and may experience lower vaccine effectiveness (VE) against COVID‐19 infection. Injection drug [...]