Abstract Background An estimated 58 749 people with opioid use disorder engaged in opioid agonist therapy (OAT) in 1132 centers in Spain during 2017. We aimed to calculate the incidence of severe injection-related infections in people who inject drugs (PWID) engaged in OAT in harm reduction settings without a safe consumption space. Methods A retrospective cohort study was performed in PWID engaged in OAT and in a mobile harm reduction unit to quantify admissions to a referral hospital for any severe injection-related infections between 1 January 2016 and 31 December 2019. A Cox proportional hazard regression analysis was used to assess factors associated with any severe injection-related infection. Results Two hundred thirty-seven PWID who engaged in OAT were included in the study. After a median follow-up of 5.5 months (interquartile range [IQR], 1.3–22.7 months), a total of 104 episodes of severe injection-related infections occurred among 56 individuals, and admission due to a second event occurred in 35.7% of this same group. The incidence density of any type of severe injection-related infection was 26.8 (95% confidence interval [CI], 20.2–34.8) episodes per 100 person-years, and the incidence density of complicated skin and soft tissue infections that required hospital admission was 20.4 (95% CI, 15.0–27.3) episodes per 100 person-years. Fifty-six (53.8%) of all the episodes were patient-directed discharge (PDD), and people who had 2 or more hospital admissions had a higher PDD frequency. Conclusions Severe injection-related infections remain highly prevalent among PWID cared for in a harm reduction setting without a safe consumption space. PDD was more frequent among higher-risk individuals who presented 2 or more hospital readmissions.