Purpose People who inject drugs (PWID) face multiple health problems, including infectious diseases and drug overdoses. Applying syndemic and risk environment frameworks, this paper aims to examine the co-occurrence and clustering of drug-related harms and their association with incarceration experience with or without in-prison drug injection. Design/methodology/approach The authors used data from a cross-sectional survey conducted in 2015 among 557 active opioid injectors. Self-reported data were collected through face-to-face or online questionnaires. They distinguished three harm categories, namely, viral infections, bacterial infections and overdoses, and built an index variable by summing the number of harm categories experienced, yielding a score from 0 to 3. Association between incarceration experience and co-occurrence of harms was modelled using a multinomial logistic regression. Findings Of the 557 participants, 30% reported lifetime experience of drug-related viral infection, 46% bacterial infection and 22% drug overdose. Multinomial logistic models showed that those who injected drugs during incarceration were more likely to report two (aOR = 2.35, 95% CI: 1.03–5.36) and three (aOR = 9.72, 95% CI: 3.23–29.22) harm categories than those who had never been incarcerated. They were also more likely to report three harm categories than formerly incarcerated respondents who did not inject drugs in prison (aOR = 5.14, 95% CI: 1.71–15.48). Originality/value This study provides insights of the syndemic nature of drug-related harms and highlights that drug injection during incarceration is associated with co-occurring harms. Public health interventions and policy changes are needed to limit the deleterious impact of prison on PWID.