Glucocorticoids (GC) are commonly prescribed and their use is associated with adverse metabolic side effects. 5a-reductase (5aR) inhibitors are also frequently prescribed mainly for their ability to inhibit the conversion of testosterone to dihydrotestosterone. However, they also have a role to inactivate and clear GCs. We hypothesised that 5aR inhibitors have the potential to exacerbate the adverse metabolic effects of GCs. We conducted a prospective, randomised, study in 19 healthy male volunteers (age; 45±8.5 years, BMI; 27.1±3.1 kg/m2). Participants underwent metabolic assessments including a 2-step hyperinsulinaemic, euglycaemic clamp incorporating stable isotopes, adipose tissue microdialysis and biopsy. They were then randomised to receive either prednisolone (10 mg daily) or prednisolone (10 mg daily) and a 5aR inhibitor (finasteride 5 mg daily or dutasteride 0.5 mg daily) for 7 days; metabolic assessments were then repeated. We have previously shown that high dose GC administration decreases glucose utilization and that 5aR inhibitors alone are without effect. In this study, prednisolone alone did not alter glucose utilization (M-value; 3.2±1.3 vs 2.8±1.6 mg/kg per min, P=0.37), but was significantly decreased by co-administration with a 5aR inhibitor (4.0±2.0 vs 2.6±1.3 mg/kg per min, P=0.02). Similarly, prednisolone did not impair the ability of insulin to suppress circulating non-esterified fatty acids (NEFA) (0.15±0.27 vs 0.13±0.13, P=0.88), unless co-administered with a 5aR inhibitor (0.15±0.1 vs 0.29±0.18, P=0.01). In addition, 5aR inhibition enhanced the ability of prednisolone to antagonize insulin-mediated suppression of lipolysis as measured by glycerol release into adipose tissue interstitial fluid (−198±133 vs. −69±85 μmol/l, P=0.04). Finally, 5aR inhibitors augmented the ability of prednisolone to induce lipogenic gene expression within subcutaneous adipose tissue (FASN: Fold change=1.3, P=0.04). We have demonstrated that 5aR inhibitors exacerbate the adverse effects of prescribed GCs. This has significant translational implications, not only with regards to the need to consider steroid dose reductions, but also the necessity for increased vigilance for the development of adverse effects.