Abundant experimental and clinical data support a modulatory role for adiponectin in inflammation, dysmetabolism, and disease. Because the activation of cells involved in innate and adaptive immunity contributes to the pathogenesis of diseases such as atherosclerosis and obesity, this study investigated the role of adiponectin in human macrophage polarization and T cell differentiation. Examination of the adiponectin-induced transcriptome in primary human macrophages revealed that adiponectin promotes neither classical (M1) nor alternative (M2) macrophage activation but elicits a pro-inflammatory response that resembles M1 more closely than M2. Addition of adiponectin to polyclonally activated CD4(+) T lymphocytes did not affect cell proliferation but induced mRNA expression and protein secretion of interferon (IFN)-γ and interleukin (IL)-6. Adiponectin treatment of CD4(+) T cells increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and signal transducer and activation of transcription (STAT) 4 and augmented T-bet expression. Inhibition of p38 with SB203580 abrogated adiponectin-induced IFN-γ production, indicating that adiponectin enhances T(H)1 differentiation through the activation of the p38-STAT4-T-bet axis. Collectively, our results demonstrate that adiponectin can induce pro-inflammatory functions in isolated macrophages and T cells, concurring with previous observations that adiponectin induces a limited program of inflammatory activation that likely desensitizes these cells to further pro-inflammatory stimuli.