Objective. Adrenomedullin22–52 is a truncated peptide derived from adrenomedullin, a growth factor with antiapoptotic and immunoregulatory properties. It can act as an agonist or an antagonist depending on cell type. Its in vivo effects are unknown, but adrenomedullin22–52 could possess immunomodulatory properties. This study was undertaken to evaluate the effect of adrenomedullin22–52 in a mouse model of arthritis. Methods. DBA/1 mice with collagen‐induced arthritis (CIA) were treated with 1.2 μg/gm adrenomedullin22–52, adrenomedullin, or saline at arthritis onset. Bone mineral density was measured at the beginning of the experiment and when mice were killed. Mouse joints were processed for histologic analysis and protein studies, and spleens were examined for Treg cell expression. Cytokine expression was studied in mouse joint tissue and serum. Results. In mice with CIA, adrenomedullin and adrenomedullin22–52 reduced clinical and histologic arthritis scores and shifted the pattern of articular and systemic cytokine expression from Th1 to Th2, as compared to untreated mice with CIA (controls). Tumor necrosis factor α, interleukin‐6 (IL‐6), and IL‐17A levels were significantly decreased in the joints of mice with CIA treated with adrenomedullin or adrenomedullin22–52 as compared to controls, whereas IL‐4 and IL‐10 levels were increased. Adrenomedullin22–52 was more effective than adrenomedullin in modulating cytokine content and enhanced Treg cell function without changing Treg cell expression compared to controls. Adrenomedullin receptor binding and transcriptional adrenomedullin receptor expression were markedly increased in joints from controls, whereas adrenomedullin receptor binding was considerably decreased in treated animals. Mice with CIA treated with adrenomedullin or adrenomedullin22–52 had considerably fewer apoptotic chondrocytes and diminished cartilage degradation. Adrenomedullin22–52 completely prevented systemic bone loss by preserving osteoblastic activity, but without changes in osteoclastic activity. Conclusion. Our findings indicate that adrenomedullin22–52, which has no vasoactive or tumor‐inducing effects, is a potent antiinflammatory and bone‐protective agent in this arthritis model.