Purpose <p>Injection site reactions (ISRs), including edema, erythema, pruritus, and pain, impact patient experience and drug tolerability. ISRs are commonly observed and pose challenges in therapeutic development, yet no non-clinical model exists for screening and derisking them before human trials. To fill in this gap, we sought to evaluate the minipig as a non-clinical model for ISRs.</p> Methods <p>The minipig model was assessed using six ISR-inducing molecules (positive controls) and two placebos with matching formulations (negative controls). Additionally, to evaluate the physiological similarity between minipigs and humans, we tested whether antihistamine pre-treatment, which is known to reduce ISRs in humans, had a similar effect in minipigs.</p> Results <p>The minipig model consistently responded to all six positive control molecules, though at higher doses than in humans. Minor ISRs occurred in a quarter of the negative controls but their frequency and/or severity was easily distinguishable from positive controls. Antihistamine pre-treatment effectively reduced ISR severity.</p> Conclusion <p>Our results suggest that the minipig model shows promise for non-clinical screening of high-risk molecules. If a molecule consistently triggers ISRs in the minipig model, phase-appropriate derisking and/or mitigation strategies are warranted. We note that the minipig model is often used for other purposes during pre-clinical subcutaneous drug development; therefore, adding ISR readouts to existing studies would incur minimal operational burden and cost. In summary, our results indicate the potential value of the minipig model in pre-clinical ISR risk assessment.</p>