The Ig isotype switch from IgM to IgE is accompanied by a DNA recombination that joins S mu, the highly repetitive "switch" region upstream of the C mu gene, to the S epsilon region upstream of C epsilon, thereby creating a composite S mu-S epsilon region. In human B cells cultured in vitro with IL-4 to promote the switch to IgE, we previously described evidence for S mu-S gamma-S epsilon structures, suggesting that some B cells can switch sequentially from mu to gamma and then to epsilon; similar sequential switching to epsilon occurs routinely in the mouse. To identify which of the four human gamma genes might be involved in this mu-gamma-epsilon switching pathway, we cloned and analyzed nine S mu-S gamma-S epsilon composite switch regions and studied S epsilon-S gamma junctions from reciprocal deletion circles. Since only the S gamma 4 sequence had previously been described, our investigation required determination of the germline S gamma 1, S gamma 2, and S gamma 3 sequences. This analysis showed that S gamma 1 is the longest and most highly repetitive switch region, including nearly identical 79-bp repeats partially homologous to the 49-bp repeat of murine S gamma sequences. Of nine cloned chromosomal S mu-S gamma-S epsilon junctions, seven were derived from S gamma 1, and one each from S gamma 3 and S gamma 4 (both of which were in inverted orientation). Analysis of reciprocal S epsilon-S gamma junctions demonstrated contributions of S gamma 1, S gamma 2, and S gamma 4. Thus, all four of the human gamma loci can participate in sequential switching to IgE, arguing against a model of directed switching from a specific subtype, such as was proposed in the murine system.