Objective: We aimed to characterize the effects of recombinant SARS-CoV-2 S1 receptor-binding domain (RBD) peptide stimulating the macrophage and microglial immune activation compared with classical PAMPs in vitro. Material: Murine RAW 264.7 macrophages and BV2 microglial cells. Treatment: The cells were exposed to growing concentrations of the RBD peptide (0.01, 0.05, and 0.1 µg/ml), LPS, and Poly(I:C) and evaluated after two h and 24h for significant markers of macrophage activation. Methods: We determined the effects of RBD peptide on cell viability, cleaved caspase 3 expressions, and nuclear morphometry analysis. RBD peptide induced a differential immune activation, dependent on the cell lineage, time of exposure, and concentration.Results: In RAW 264.7 cells, RBD peptide stimulation was cytotoxic but not for BV2 cells. RAW 264.7 cells showed increased arginase activity and IL-10 production; however, BV2 cells express iNOS and IL-6 after RBD peptide exposure. RAW 264.7 cells showed increased cleaved-caspase-3, apoptosis, and mitotic catastrophe after RBD peptide stimulation but not BV2 cells. In conclusion, RBD peptide exposure has different effects depending on cell line stimulated, RAW 264.7, and BV2 cells.Conclusion: This study brings new evidence about the immunogenic profile of RBD in macrophage and microglial cells, advancing the understanding of SARS-Cov2 immuno- and neuropathology.