A genetic deficiency of the fifth (C5) component of complement^1–3, a serum glycoprotein of molecular weight (MW) 220,000 (ref. 4), has been found in 39% of inbred strains of mice³. Sera of deficient mice lack detectable C5 activity and protein^2,3. In addition deficient mice produce antibody to mouse C5 when injected with sera from C5 sufficient (normal) strains. Levy et al.⁵ showed that somatic cell hybrids between C5 deficient (B10.D2/old line) macrophages and either C5 sufficient (B10.D2/new line) mouse kidney or chicken erythroblasts secreted haemolytically active mouse C5 in vitro. Several possible molecular mechanisms to account for the findings were considered, but insufficient direct data were available to choose among them. We recently reported that mouse (CD.1 strain) peritoneal cells in culture synthesise and secrete a single chain precursor, pro-C5 (MW ∼ 210,000), of the two-chain (α chain, 125,000 and β chain 83,000 MW) C5 protein⁶. Radiolabelled precursor C5 was contained within the cells and was secreted into the tissue culture media. Using similar methods, we now find that C5 deficiency in each of five different mouse strains (AKR, SWR, DBA/2J, A/HeJ and B10.D2/old line) is due to a failure in secretion of C5 protein and not to a failure in biosynthesis of pro-C5.