The immunoreactive responses are a two-edged sword after spinal cord injury (SCI). Macrophages are the predominant inflammatory cells responsible for this response. However, the mechanism underlying the effects of HBOT on the immunomodulation following SCI is unclear now. The present study was performed to examine the effects of hyperbaric oxygen therapy (HBOT) on macrophage polarization after the rat compressive injury of the spinal cord. HBOT was associated with significant increases in IL-4 and IL-13 levels, and reductions in TNF-alpha and IFN-gamma levels. This was associated simultaneously with the levels of alternatively activated macrophages (M2 phenotype: arginase-1- or CD206-positive), and decreased levels of classically activated macrophages (M1 phenotype: iNOS- or CD16/32-positive). These changes were associated with functional recovery in the HBOT-transplanted group, which correlated with preserved axons and increased myelin sparing. Our results suggested that HBOT after SCI modified the inflammatory environment by shifting the macrophage phenotype from M1 to M2, which may further promote the axonal extension and functional recovery. (C) 2015 Elsevier B.V. All rights reserved.