The maturation of IgM-expressing B cells to IgM-secreting plasma cells is associated with both an increase in mu mRNA and the ratio of secreted to membrane forms of mu mRNA which differ at the 3' termini. In contrast, both in vitro and in vivo the secreted form of alpha mRNA is predominant at all stages in the development of a secretory IgA response. Previous studies demonstrated that preferential usage of the alpha s poly(A) site does not result from transcription termination and is independent of either the poly(A) sites or the 3' splice site associated with the exon encoding the membrane exon of IgA (alpha M). The present study demonstrates that a 349-bp region located 774 bp 3' to the alpha s poly(A) site is required for the preferential usage of the alpha s terminus. This region, which is the first isotype-specific cis-acting regulatory sequence not immediately adjacent to a secretory poly(A) site to be identified, contains regulatory elements that increase the efficiency of polyadenylation/cleavage. A ubiquitous, approximately 58-kDa RNA-binding protein interacts specifically with this regulatory region. These studies support the premise that cis-acting elements unique to each CH gene can impinge upon a common mechanism regulating Ig mRNA processing.