Our aim was to assess the value of a single determination of plasma cyclic guanosine 3',5'-monophosphate (cGMP) in noninvasive screening for acute cardiac allograft rejection warranting augmentation of immunosuppression. Plasma cGMP levels were measured in 26 patients 1 to 13 months after heart transplantation on the same day the endomyocardial biopsies were performed. Acute moderate rejection (ISHLT 3A or 3B) was found in 10 out of 17 subjects (59%) with plasma cGMP >5 nmol/L, whereas there was mild or no rejection (ISHLT 0 to 1) in 8 from among 9 subjects (89%) with cGMP <5 nmol/L. Because cGMP levels <5 nmol/L appear to argue against the presence of acute rejection requiring therapy modification, our preliminary results suggest that a single plasma cGMP assay might be helpful in establishing indications for endomyocardial biopsy in heart transplant recipients.