The use of an intra-articular methylprednisolone acetate (MPA) injection has been shown to have benefits for symptoms of knee osteoarthritis (OA). However, considerations beyond drug efficacy can influence the appropriateness, clinical effectiveness and potential harm of an injection. A review of research evidence and published literature on clinical and procedural factors influencing the effectiveness and safety of a knee injection has been undertaken. Factors include dose, frequency, contraindications, precautions, drug interactions, side-effects, and procedural and patient-related considerations. An evaluation of evidence indicated that a 40 mg dose provides clinical benefit. No strong predictors of response were evident, with the exception of pain severity. Additional benefit for outcomes from higher doses, local anaesthetic, ultrasound guidance or particular anatomical approaches is yet to be demonstrated. Evidence for dose- and duration-related detrimental effects suggests judicious use and frequency. The evaluation showed that there are a number of contraindications and precautions arising from the drug pharmacology, concurrent medications, comorbidities and adverse events which need consideration and monitoring. There was limited safety evidence concerning anticoagulation. The review found that specialist guidance and limited evidence suggests that injection safety concerning warfarin may be enhanced by ensuring that the international normalized ratio level is within therapeutic range. However, the risk-benefit evaluation concerning non vitamin K antagonist oral anticoagulants remains challenging. Although there is published guidance, a lack of clinical studies, safety evidence and reversibility advocates caution. Overall, the review indicates that injection decisions and procedures need an individualized approach and supporting evidence is limited in many areas. Evaluation and discussion of benefits and risks, peri-procedural and post-injection management, and tailoring to the context and individuals' preferences are important in optimizing the benefits and safety of a knee injection.