The cAMP phosphodiesterase (PDE) inhibitors potentiated the calcitonin gene-related peptide (CGRP)-inhibitory effect on lipopolysaccharide (LPS)-induced interleukin-12 (IL-12) release, and forskolin or 8-Br-cAMP inhibited LPS-induced IL-12 release from mouse peritoneal macrophages (Mφ). Mφ were pretreated with 10 µm IBMX or 30 µm rolipram for 30 min, and then 0·1 µg/ml of LPS, with 100 nm CGRP, was added for 24 hr. In order to test the effect of forskolin or 8-Br-cAMP on LPS-induced IL-12 release, Mφ were stimulated with LPS alone (0·1 µg/ml) or with LPS and either 1 µm forskolin or 1 mm 8-Br-cAMP, for 24 hr. The IL-12 level in the medium was assayed by using an enzyme-linked immunosorbent assay (ELISA). The inhibitory effect of CGRP on LPS-induced IL-12 release was significantly potentiated by the two cAMP PDE inhibitors. Both forskolin and 8-Br-cAMP markedly suppressed the LPS-induced IL-12 release. The data shown represent mean values ± SEM. *P < 0·05 compared with the LPS + CGRP group, n = 4 for each group; †P < 0·05 compared with LPS alone, n = 4–6 for each group.