The expanding clinical use of interleukin-1β (IL-1β) monoclonal antibodies (mAbs) for chronic diseases raises important questions about their long-term safety, particularly infection risk. Despite IL-1β serves as a central driver of inflammatory responses, multiple large-scale clinical trials have demonstrated that specific blockade of IL-1β does not substantially increase overall infection risk in patients. This review explores the mechanistic basis for this favorable benefit‑risk profile. It highlights the constitutive immune mechanisms that provide a stable first line of defense independent of IL-1β induction, the high complementarity within the IL-1 family enabling selective blockade benefits, and the pharmacokinetic profiles of biologics ensuring selective lesion distribution. Furthermore, it discusses the precise neutralization of systemic spillover inflammation while preserving local autocrine/paracrine homeostasis, the evolving disease spectrum in which sterile inflammation has surpassed infection as a primary health challenge, and the need for clinical vigilance against specific pathogen infections. Overall, specific blockade of IL-1β achieves effective anti‑inflammatory therapy without compromising fundamental host defense.