We demonstrated that adrenomedullin (AM) inhibited interleukin-1β-induced tumor necrosis factor-α (TNF-α) secretion and gene transcription in Swiss 3T3 fibroblasts maximally to 23% and 18% of control, while the other peptides elevating intracellular cAMP levels elicited much weaker effects. AM rapidly reduced the gene transcript level of TNF-α, inducing a maximal effect within 1 h. The inhibitory effect of AM was restored with an AM receptor antagonist as well as a cAMP-dependent protein kinase inhibitor. These findings indicate that AM is a potent and quick suppressor of TNF-α production in Swiss 3T3 cells acting through the cAMP protein kinase A pathway. As TNF-α is a major inflammatory cytokine and stimulates AM production in fibroblasts, AM is deduced to be an autocrine or paracrine factor suppressing inflammation through the inhibition of TNF-α production.