Adherence to vaccination recommendations is a challenge for national immunization programs. We quantified adherence to COVID-19 vaccination recommendations in people with substance use disorders (SUDs) attending an outpatient addiction center in Rome, Italy; we investigated the determinants of adherence, and also analyzed patient risk perception and compliance with preventive measures. A multivariable logistic regression model identified predictors of adherence to vaccination recommendations, with statistical validity tested by estimating adjusted odds ratios (aORs) and 95% confidence intervals (CIs). From December 2021 to January 2022, 200 SUD patients completed a questionnaire, 80% of whom reported being vaccinated against SARS-CoV-2 (minimum one dose). Negative predictors of vaccine uptake included being non-Italian (aOR: 0.36, 95% CI: 0.13–0.97), having coexisting comorbidities (aOR: 0.35, 95% CI: 0.13–0.95), and previous use of heroin (aOR: 0.24, 95% CI: 0.08–0.71). No difference was found for cocaine use, demographic characteristics, previous COVID-19 infection, methadone therapy, or compliance with preventive measures. Major reasons for non-adherence to vaccination recommendations were fear of side effects, insufficient recognition of the importance of vaccination, bureaucratic issues, and lack of trust in the authorities. Given their vulnerability, additional efforts are needed to facilitate access to vaccination for people with SUDs, and to limit disinformation around vaccines..