It is known that cannabinoid type 2 (CB2) receptor has anti-inflammatory role, therefore animals without CB2 receptors show enhanced inflammation and pain in the model of chronic pain e.g. neuropathic pain. We previously proposed the upregulated leptin signaling at the peripheral nerve as one of the underlying molecular mechanisms of pain exacerbation in nerve-injured CB2 knockouts, as they displayed robust upregulation of leptin receptors and leptin signaling in peripheral nerve. Due to these past results we hypothesized that CB2 receptor deficiency might also modify the peripheral neuroinflammation lead by chronic exposure to high fat diet (HFD). Interestingly, CB2 knockout animals showed the significant resistance to the HFD-induced neuroinflammation. Namely, 5-week feeding of HFD induced substantial hypersensitivity in WT animals, while tactile sensitivity of HFD-fed CB2 knockouts remained intact. HFD-fed WT animals also displayed the robust upregulation of chemokine CXCR4 expression with increased macrophage infiltration, which was never observed in HFD-fed CB2 knockout mice. Moreover, 5-week HFD-exposure lead significant increase of CD11b+Ly6G-Ly6Chighcells and decrease of CD11b+Ly6G+Ly6Clowcells in the spleen of WT animals, which was also not found in either HFD-fed CB2 knockouts or standard diet-fed WT and CB2 animals. Together with past report, these results suggest that CB2 receptors might have the double-sided regulatory role in context of the inflammation development, or more widely, immune system regulation. We propose that CB2 signaling is not always anti-inflammatory and could take pro-inflammatory role depending on the cause of the inflammation.