The distribution of substance P (SP)- and neuropeptide Y (NPY)-immunoreactive (IR) nerve fibers in the rabbit tenuissimus muscle was investigated by means of immunohistochemistry. Electron microscopy was used to study the ultrastructural appearance of nerve fibers and terminals. SP-IR nerve fibers were sparse in the main feeding vessels to the muscle and in the central artery and vein, but moderately dense in the motor nerve and in nerve bundles running in the vicinity of the vessels. Occasionally, fibers were seen in apposition to arterioles and venules in the muscle. NPY-IR nerves formed a dense network of a typically adrenergic appearance encircling the feeding artery, central artery, and arterioles of all sizes. NPY-IR nerves were not seen around venules or veins. In the motor nerve, NPY immunoreactivity could be seen after ligation. Electron microscopy showed nerve terminals containing both small vesicles and large dense core vesicles outside the media of arterioles and, more seldom, of venules. Also, unmyelinated fibers followed myelinated nerve bundles along arterioles. The fact that there are a great many SP- and NPY-immunoreactive fibers in the tenuissimus muscle, with a distribution that harmonizes with their pharmacological actions, supports the view that local release of these neuropeptides contributes significantly to microvascular regulation in skeletal muscle.