The t(14;18) translocation juxtaposes the bcl-2 gene on chromosome 18 to a joining (J) gene segment of the immunoglobulin heavy chain gene (IgH) on chromosome 14. Up to 85% of non-Hodgkin's lymphomas (NHL) are t(14;18) positive. Recent reports have documented point mutations in the second exon of translocated bcl-2 alleles and postulated that immunoglobulin variable (V) region somatic hypermutation, related to Ig sequences approximately 250 Kb downstream, may be mediating these mutations. We have examined the third exon of bcl-2, directly adjacent to Ig sequences in the t(14;18), for point mutations. In particular, we studied the translated region of exon 3 in 45 NHLs by SSCP analysis and failed to detect a single point mutation. Further, we sequenced eleven t(14;18) breakpoints, including both bcl-2 and JH sequences, and detected only one point mutation, in a JH-derived sequence. We conclude that immunoglobulin V region somatic hypermutation does not induce point mutations into the t(14;18) breakpoint region or into the translated region of the third exon of bcl-2 alleles involved in the t(14;18) translocation, conserving the membrane insertion properties of the carboxyl tail of this protein.