Abstract. Cyclophilins (cyclosporin A-binding proteins) are conserved, ubiquitous, and abundant proteins that accelerate the isomerization of XaaPro peptide bonds and the refolding of proteins in vitro. s-Cyclophilin is a member of the cyclophilin family with unique NH2-and COOH-terminal extensions, and with a signal sequence. We now report that s-cyclophilin is retained in the cell, and that the conserved s-cyclophilin-specific COOH-terminal extension VEKPFAIAKE is sufficient to direct a secretory protein to s-cyclophilin containing structures .Antibodies to s-cyclophilin-specific peptides were produced and the location of the protein was determined by an immunocytochemical study at the light microscopic level . s-Cyclophilin colocalized with the Cat+-binding protein calreticulin and, to a lesser extent, with the microsomal Cat+ATPase in the myogenic cell line L6, and with the Cal+-binding protein calsequestrin in skeletal muscle . In activated platelets, s-cyclophilin immunoreactivity was detected in a ringlike structure that might correspond to the Cal+-storing and -releasing dense tubular network . In spreading cells, s-cyclophilin containing vesicular