Among three lipases in the lipase gene family, hepatic lipase (HL), lipoprotein lipase (LPL) and pancreatic lipase (PL), HL exhibits the lowest intracellular specific activity, i.e. minimal amounts of catalytic activity accompanied by massive amounts of i nactive lipase mass in the endoplasmic reticulum (ER). In addition, HL has a distinctive sedimentation profile, where the inactive mass overlaps the region containing active dimeric HL and trails into progressively larger molecular forms. Eventually, at least half of the HL inactive mass in the ER reaches an active, dimeric conformation (t1/2=2 hours), and is rapidly secreted. The remaining inactive mass is degraded. HL maturation occurs in the ER, and is strongly dependent on binding to calnexin in t he early co/post-translational stages. Later stages of HL maturation occur without calnexin assistance, although inactive HL at all stages appears to be associated in distinct complexes with other ER proteins. Thus, unlike other lipases in the gene fami ly, HL maturation is the rate-limiting step in its secretion as a functional enzyme.