The calcineurin inhibitors cyclosporinA (CsA) and tacrolimus (FK-506) are widely used as immunosuppressive drugs in transplanted patients and are associated with cardiovascular side effects. The calcineurin inhibitor cyclosporinA inhibits COX-2 gene expression in cell cultures. COX-2 inhibitors suppress systemic cardioprotective prostacyclin (PGI₂) in humans. We hypothesized that calcineurin inhibitors lower anti-thrombotic PGI₂ and elevate pro-aggregatoric thromboxane (TxA₂) in human patients. In experiments with cultures of human vascular smooth muscle cells, fetal calf serum (20%)-stimulated PGI₂ production (6-ketoPGF1?a) was significantly diminished in response to CsA (10^-7M), prednisolon(10^-5M), and the selective COX-2 inhibitor NS-398 (10^-6M), (all p > 0,05), whereas FK-506 (10^-7M) had no effect. Blood and urine samples were obtained from 19 kidney transplant patients (KTPs) treated with CsA or FK-506, 10 KTPs treated with CsA or FK-506 and steroid, and 12 healthy controls. ELISA measurements of the stable urinary and plasma metabolites, 6-ketoPGF1?a and 2,3 dinor TXB₂ respectively, were performed. At the peak of plasma drug concentrations (2h after dosing), there were no differences in the level of metabolites between the KTPs treated with CsA or FK-506 and the control group in urine (82.5 vs. 88.8 ng/2h for PGI₂ and 146.5 vs. 150.8 ng/2h for TxA₂) or in plasma (266.8 vs. 191.7 ng/2h for PGI₂ and 87.8 vs. 129.2 ng/2h for TxA₂). These findings suggest that calcineurin inhibitors and glucocorticosteroids are potent inhibitors of COX-2 activity <i>in vitro</i>, but not <i>in vivo</i> in renal allograft patients with therapeutic levels of these drugs.