Aim: The study aims to show that sodium selenite (Ss) would have an immunomodulatory effect on the functional activity of proinflammatory macrophages (Mφs) during their extended extracellular activation at the onset of human type 1 diabetes (T1D). Background: Exacerbated activation of proinflammatory "M1" macrophages (Mφs) can promote chronic local pancreatic islet inflammation and T1D development. Objective: We investigated the ex vivo effects of Ss on the immune modulation of global/extended activation of human proinflammatory M1-like Mφs. Methods: Experiments were carried out on primary monocytes-derived Mφs (MDMs). Results: The levels of IL-1β, TNF-α, H2O2 and intracellular free calcium ions (ifCa2+), and the ratios of IL-1β-to-IL-10 and TNF-α-to-IL-10 were markedly increased in T1D Mφs than in healthy control Mφs. Conversely, both IL-10 production and arginase 1 (ARG1) activity were downregulated in T1D Mφs. Additionally, Ss treatment induced a marked downregulation of respiratory burst, ifCa2+ levels, M1-like Mφ-associated inducible nitric oxide (NO) synthase (iNOS) activity, cell necrosis and related necroinflammation biomarkers, including IL-1β and TNF-α, CD14 expression, and the ratios of iNOS-to-ARG1, IL-1β-to-IL-10, and TNF-α-to-IL-10. Moreover, Ss upregulated anti-inflammatory "M2-like" Mφ activity as demonstrated by ARG1 activity and IL-10 production, as well as phagocytosis capacity. Conclusion: Ss exerts a potent immunomodulatory role on functional activities of human proinflammatory T1D M1-like Mφs subjected to extended activation, as well as on the M1-like/M2-like dichotomy. Additionally, the current study provides a novel therapeutic approach using Ss to promote the anti-inflammatory function of Mφs at the onset of T1D.Keywords: Extended extracellular activation spectrum; immunomodulation; macrophage functional activities; primary human M1-like monocyte-derived macrophages; sodium selenite treatment; type 1 diabetes.