We have examined the position of the chromosomal breakpoint relative to the human c-myc gene (MYC) and the presence of other structural alterations of the same locus in 19 fresh samples of Burkitt lymphoma (BL) and 13 BL-derived cell lines. This panel includes the two pathogenetic forms of BL: the endemic (African-type) BL (eBL) and sporadic (American-type) BL (sBL). In all cases tested, including fresh samples and cell lines, structural alterations of the 5' portion of the gene were detected, suggesting that they may be necessary for c-myc activation. However, the site of chromosomal breakpoint and the type of structural alterations differ in eBL and sBL. In 16 of 18 sBL cases, chromosomal translocation truncates the gene within a 5' region that includes the first intron, the first exon, and 5' flanking sequences. Conversely, in 14 of 14 eBL samples, the chromosomal breakpoint is located outside the c-myc locus, yet the same 5' sequences are affected by several mutations identifiable by restriction enzyme polymorphisms. Different genetic mechanisms may therefore be involved in chromosomal translocation/c-myc activation, and these differences may be a function of differences in the stage of differentiation of eBL versus sBL.