The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the various Ig heavy chain constant region exons. Molecular analyses of S-region functions have been hampered by their large size and repetitive nature. To test potential relationships between S-region size and efficiency of CSR, we generated normal B lymphocytes in which the 12-kb S region flanking the Cgamma1 exons (Sgamma1) was replaced with synthetic or endogenous S regions of various lengths. Replacement of Sgamma1 with 1- and 2-kb synthetic sequences representing the Sgamma1 core repeats or a 4-kb portion of the core endogenous Sgamma1 region supported CSR frequencies that directly correlated with S-region length. These findings indicate that S-region size is an important factor in determining endogenous CSR efficiency. Moreover, these results also will allow the development of a systematic system to test the function of various S-region motifs by replacing endogenous S regions with synthetic S regions controlled for size effects.