t(11;18)(q21;q21) is the most frequent chromosomal aberration specifically associated with mucosa-associated lymphoid tissue (MALT) lymphoma. The translocation fuses the API2 gene to the MALT1 gene and generates a functional API2-MALT1 transcript. The breakpoint of the fusion gene is well characterized at the transcript level but poorly understood at the genomic level and the mechanism underlying the translocation is unknown. We identified the genomic breakpoint in 19 t(11;18)-positive MALT lymphoma cases by polymerase chain reaction and sequencing and analysed the junctional sequences. The breakpoints were scattered in intron 7 and exon 8 of the API2 gene, and introns 4, 6, 7 and 8 of the MALT1 gene. Comparative sequence analysis between the API2-MALT1 fusion on der(11) and the MALT1-API2 fusion on der(18) showed extensive alterations including deletions, duplications and non-template-based insertions at the fusion junctions in all cases examined. An extensive sequence search failed to reveal any known sequence motifs that might be associated with chromosomal recombination or any novel consensus sequences at or near the breakpoints on both der(11) and der(18) except in one case, in which Alu repeats spanned the breakpoint of the MALT1-API2 fusion. Our results suggest that t(11;18) may result from illegitimate non-homologous end joining following double strand breaks.