In 34 psoriatic patients with various cutaneous manifestations (psoriasis vulgaris, erythroderma psoriaticum, guttate psoriasis), the ability of the RI regulatory subunit of cAMP-dependent protein kinase (PKA) to bind a cAMP analogue (8-azido [32P] cAMP) in erythrocyte membranes was significantly lower than that in 19 normal subjects (mean [SEM] 565 [35] vs 930 [35] fmol/mg protein). This enzyme defect was not found in patients with other forms of dermatitis that can be confused with psoriasis or with other inflammatory diseases. There was a significant negative correlation between the severity of the disease as expressed by the psoriatic area and severity index score and the binding of the cAMP analogue to PKA. A long-term study showed that oral retinoid treatment of psoriatic patients resulted in a correction of the binding defect. Unaffected members of psoriatic families had significantly lower than normal binding of cAMP to PKA (773 [60] fmol/mg protein). This study shows for the first time that in psoriasis a biochemical defect expressed in erythrocytes correlates with the severity of the disease as well as its clinical evolution. These results will be useful in clinical management of psoriatic disease for the choice and follow-up of retinoid therapy.