Background and objectives: Recent studies have shown that lupine protein hydrolysates (LPH) could be an important source of bioactive peptides, especially showing anti-inflammatory activity. The present study aimed to test whether peptide GPETAFLR released from the enzymatic hydrolysis of lupine protein may modulate the inflammatory response in human primary monocytes. Methods: Freshly human monocytes were used to analyze the effects of GPETAFLR, after 24 hours of treatment at 50-100 μg/mL, on LPS-induced inflammatory response using FACS analysis, RT-qPCR, and ELISA procedures. Results: We report that GPETAFLR from LPH possesses anti-inflammatory properties in human monocytes. GPETAFLR skewed the monocyte plasticity towards the anti-inflammatory non-classical CD14+CD16++ monocytes and reduced the inflammatory competence of LPS-treated human monocytes diminishing IL-1β, IL-6, and TNF-a production and gene expression. Results: Conclusions: Taken together, our results show that GPETAFLR has the potential to impair the activation of human primary monocytes and the derived inflammatory conditions, and suggest a new role for Lupinus angustifolius L. protein hydrolysate in the regulation of the pathogenesis of health disorders in which monocytes play a key role, including atherosclerosis and several chronic diseases.