cDNAs for the bcl-2 mRNA were cloned from a human common acute lymphoblastic leukemia cell line. Nucleotide sequence analyses showed that the 6 kb bcl-2 mRNA potentially encodes a 26 kd protein that is homologous to a predicted Epstein-Barr virus protein. Most t(14;18) translocation breakpoints cluster within a narrow region of a 5.4 kb exon that contains a long 3′-untranslated region of the bcl-2 mRNA. As a result of t(14;18) translocation, hybrid bcl-2/immunoglobulin heavy chain transcripts are produced that consist of the 5′ half of the bcl-2 mRNA fused to a “decapitated” immunoglobulin heavy chain mRNA. Nucleotide sequence analyses confirmed that the hybrid transcripts continue to encode a normal bcl-2 protein. Our results suggest that t(14;18) translocations alter expression of the bcl-2 gene both by transcriptional activation and by abnormal posttranscriptional regulation of bcl-2 mRNA.