The activity of cyclic AMP-dependent protein kinase (protein kinase A) in the sensitized rat mast cell was decreased 2 min after antigen challenge when the histamine release exhibited a maximum. Drugs inhibiting allergic mediator release such as disodium cromoglycate, tranilast and theophylline significantly inhibited antigen-induced histamine release and reduced a decrease in the activity of protein kinase A. These results suggest that protein kinase A is involved in the histamine releasing process in the mast cell, and drugs inhibiting allergic mediator release cause their effects partially through the inhibition of protein kinase A.