The requirement of divalent cations for binding of the 46 kDa mannose 6-phosphate receptors to phosphomannan and pentamannose 6-phosphate-substituted bovine serum albumin was examined. Receptors from human liver and human brain bound to both affinity ligands in the absence or presence of divalent cations with similar efficiency. The requirement for divalent cations therefore appears not to be necessary for the binding.