High levels of drug dependence have been observed in the prison population globally, and the sharing of injecting drug equipment in prisons has contributed to higher prevalence of bloodborne diseases in prisoners than in the general population. Few prison needle and syringe programs (PNSPs) exist. We conducted a systematic review to assess evidence regarding health outcomes of PNSPs. We searched peer-reviewed databases for data relating to needle and syringe programs in prisons. The search methodology was conducted in accordance with accepted guidelines. Five studies met review inclusion criteria, and all presented evidence associating PNSPs with one or more health benefits, but the strength of the evidence was low. The outcomes for which the studies collectively demonstrated the strongest evidence were prevention of human immunodeficiency virus and viral hepatitis. Few negative consequences from PNSPs were observed, consistent with previous evidence assessments. More research is needed on PNSP effectiveness, and innovative study designs are needed to overcome methodological limitations of previous research. Until stronger evidence becomes available, policymakers are urged to recognize that not implementing PNSPs has the potential to cause considerable harm, in light of what is currently known about the risks and benefits of needle and syringe programs and PNSPs and about the high prevalence of human immunodeficiency virus and viral hepatitis in prisons.