Hypopituitarism is associated with increased cardiovascular mortality. It has been suggested that hypogonadism, hypothyroidism, growth hormone deficiency (GHD), or indeed unphysiological hormone replacement regimens, might contribute to this excess cardiovascular risk. The adverse effect of hypercortisolaemia on insulin resistance, carbohydrate metabolism and hypertension is well recognised. It is also known that glucocorticoids adversely affect the coagulation-fibrinolytic system, with an increased risk of thromboembolism in Cushings syndrome. GHD reduces fibrinolytic activity and might predispose to a pro-coagulant state reversed by growth hormone replacement. We examined the hypothesis that short term higher dose hydrocortisone replacement might adversely affect the fibrinolytic system and be an additional factor leading to the excess cardiovascular mortality in hypopituitarism. We measured serum cortisol, plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen levels in 10 hypopituitary adults whilst treated with either a fixed high dose hydrocortisone regimen of 30 mg / day (HD) or a patient-tailored lower dose (mean dose 18 mg / day) regimen (LD). We also studied 10 controls. PAI-1; [median (range)] HD 25 (553) ng/ml versus LD 21 (456) ng/ml; P=1.0, tPA; HD 10 (55) ng/ml versus LD 10 (413) ng/ml; P=0.3 and fibrinogen; HD 2.5 (1.83.5) g/l versus LD 3.0 (2.34.4) g/l; P < 0.001. Short term higher dose hydrocortisone replacement dose did not affect PAI-1 or tPA levels and suggests that such differences in hydrocortisone replacement doses are unlikely to lead to significant effects on the fibrinolytic system, at least in the short term. The small but significant increase in fibrinogen during low dose therapy was unexpected and might not be clinically significant. In terms of fibrinolytic activity, this study does not does support the suggestion that traditional higher dose hydrocortisone replacement regimens might adversely affect cardiovascular risk in hypopituitary patients.