In multicellular organisms, secreted proteins play pivotal regulatory roles in intercellular communication. Proteins secreted by skeletal muscle can act locally on muscle cells through autocrine/paracrine loops and on surrounding tissues such as muscle blood vessels, or they can be released into the blood stream, thus producing systemic effects. By a computational approach, we have screened 6255 products of genes expressed in normal human skeletal muscle. Putatively secreted proteins were identified by sequential steps of sieving, through prediction of signal peptide, recognition of transmembrane regions, and analysis of protein annotation. The resulting putative skeletal muscle secretome consists of 319 proteins, including 78 still uncharacterized proteins. This is the first human skeletal muscle secretome produced by computational analysis. Knowledge of proteins secreted by skeletal muscle could stimulate development of novel treatments for different diseases, including muscle atrophy and dystrophy. In addition, better knowledge of the secretion process in skeletal muscle can be useful for future gene therapy approaches. Proteins 2006. © 2005 Wiley‐Liss, Inc.