1 Chalcone is abundantly present in the plant kingdom and has various biological activities such as anti-inflammatory and antioxidant. In this study, the semisynthetic chalcone derivative, 3'-isopropoxychalcone (H2O7D), was demonstrated to inhibit the generation of superoxide and the release of elastase, as well as to accelerate resequestration of cytosolic calcium in formyl-L-methionyl-L-leucyl-L-phenylalanine-activated human neutrophils. 2 H2O7D displayed no antioxidant or superoxide-scavenging ability, and it failed to alter the subcellular NADPH oxidase activity. 3 H2O7D induced a substantial increase in cAMP but not cGMP levels. The elevation of cAMP formation by H2O7D was inhibited by adenosine deaminase (ADA). Furthermore, The inhibitory effects of H2O7D were reversed by protein kinase (PK)A inhibitors, as well as ADA and a selective A2a-receptor antagonist. 4 H2O7D inhibited phosphodiesterase (PDE) activities, but it did not alter adenylyl cyclase and soluble guanylyl cyclase activities. These results show that the cAMP-elevating effect of H2O7D results from the inhibition of PDE activity and not from the stimulation of cyclase function. Consistent with this, H2O7D potentiated the PGE(1)-caused inhibitory effects and cAMP formation. 5 In summary, these results indicate that the inhibitory effect of H2O7D is cAMP/PKA dependent, and that it occurs through inhibition of cAMP PDE, which potentiates the autocrine functions of endogenous adenosine. Inhibition of respiratory burst and degranulation in human neutrophils may give this drug the potential to protect against the progression of inflammation.