The apolipoprotein E2 ( apoE2 ) variant that possesses a cysteine substituted for an arginine at residue 158 in the amino acid sequence E2( Arg158 ----Cys) can be distinguished by sodium dodecyl sulfate-polyacrylamide gel electrophoresis from other forms of apoE, including E3 (the parent form), E4( Cys112 ----Arg), E2( Arg145 ----Cys), and E2( Lys146 ----Gln). The E2( Arg158 ----Cys) migrates as a distinctly separable band with a higher apparent molecular weight than the other forms. Chemical modification of apoE2 ( Arg158 ----Cys) with sulfhydryl reagents (2-bromoethyl)-trimethylammonium bromide or cysteamine, which convert cysteine to arginyl or lysyl analogues, respectively, abolishes the difference in apparent molecular weight and results in the co-electrophoresis of E2( Arg158 ----Cys) with other apoE forms. The mobilities of the other apoE variants are not affected by these modifications. These results suggest that the substitution site at residue 158 is a key location, important in modifying the behavior of apoE and in modulating its apparent molecular weight on sodium dodecyl sulfate-polyacrylamide gels. Furthermore, the technique used in this study may be very helpful in distinguishing specific mutant forms of apoE2 .