Skeletal muscle hormone sensitive lipase (HSL) activity is increased by contractions, and increases in blood epinephrine (EPI) concentrations and cyclic AMP-activation of the adrenergic pathway during prolonged exercise. To determine the importance of hormonal stimulation of HSL activity during the onset of exercise, nine males (age 24.3 ± 1.2 yr, 80.8 ± 5.0 kg, VO_2peak 43.9 ± 3.6 ml^. kg^-1. min^-1) cycled for 1 min at ~65% VO_2peak, rested, and cycled at ~90% VO_2peak for 1 min. Skeletal muscle biopsies were taken pre and post-exercise and arterial blood was sampled throughout. Arterial EPI increased (p < 0.05) post-exercise at 65% (0.45 ± 0.10 to 0.78 ± 0.27 nM) and 90% VO_2peak (0.57 ± 0.34 to 1.09 ± 0.50 nM). HSL activity increased (p < 0.05) following 1 min of exercise at 65% VO_2peak (1.05 ± 0.39 to 1.78 ± 0.54) and 90% VO_2peak (1.07 ± 0.24 to 1.91 ± 0.62 mmol^. min^-1.kg dry muscle (dm^-1). cAMP content also increased (p < 0.05) at both exercise intensities (65%: 1.52 ± 0.67 to 2.75 ± 1.12, 90%: 1.85 ± 0.65 to 2.64 ± 0.93 µmol^. kg dm^-1). HSL Ser 660 phosphorylation (~55% increase) and ERK1/2 phosphorylation (~33% increase) were augmented following exercise at both intensities, whereas HSL Ser 563 and Ser 565 phosphorylation were not different from rest. The results indicate that increases in arterial EPI concentration during the onset of moderate and high intensity exercise increase cyclic AMP content which results in the phosphorylation of HSL Ser 660. This adrenergic stimulation contributes to the increase in HSL activity that occurs in human skeletal muscle in the first minute of exercise at 65% and 90% VO_2peak.