ATP-sensitive potassium (K_ATP) channels have been suggested to contribute to coronary and skeletal muscle vasodilation during exercise, either alone or interacting in a parallel or redundant process with nitric oxide (NO), prostaglandins (PGs), and adenosine. We tested the hypothesis that K_ATP channels, alone or in combination with NO and PGs, regulate exercise hyperemia in forearm muscle. 18 healthy young adults performed 20 min of moderate dynamic forearm exercise, with forearm blood flow (FBF) measured via Doppler ultrasound. After achieving steady state FBF for 5 min (saline control), the K_ATP inhibitor glibenclamide (Glib) was infused into the brachial artery for 5 min (10µg dl^-1 min^-1), followed by saline infusion during the final 10 min of exercise (n=9). Exercise increased FBF from 71±11 to 239±24 ml min^-1, and was not altered by 5-min of Glib. Systemic plasma Glib levels were above the therapeutic range, and Glib increased insulin levels by ~50%, while blood glucose was unchanged (88±2 vs 90±2 mg dl^-1). In 9 additional subjects, Glib was followed by combined infusion of L-NAME plus ketorolac (to inhibit NO and PGs, respectively). As above, Glib had no effect on FBF but addition of L-NAME + ketorolac (i.e. Triple Blockade) reduced FBF ~15% below steady state exercise levels in 7 of 9 subjects. Interestingly, triple blockade in 2 subjects caused FBF to transiently and dramatically decrease. This was followed by an acute recovery of flow above steady state exercise values. We conclude 1) opening of K_ATP channels is not obligatory for forearm exercise hyperemia, and 2) triple blockade of NO, PGs, and K_ATP channels does not reduce hyperemia more than the inhibition of NO and PGs in most subjects. However, some subjects are sensitive to triple blockade, but are able to restore FBF acutely during exercise. Future studies are required to determine the nature of these compensatory mechanisms in the affected individuals.