Several balanced translocations have been identified in extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) but there are few data regarding their frequency in different anatomic sites or the frequency of translocations involving BCL6 or kappa or lambda immunoglobulin light chain genes (IGK or IGL), particularly in patients from geographic regions other than Europe and Japan. One hundred thirty-three paraffin-embedded North American primary MALT lymphoma specimens from diverse anatomic sites were studied by fluorescence in situ hybridization (FISH) using probes for API2-MALT1, IGH-MALT1, IGH-BCL10, IGH-FOXP1, IGH, +/- centromeres 3, 7, 12, and 18, and a subset (n=74) were analyzed using FISH probes for IGK, IGL, and BCL6. Translocations were mutually exclusive and were detected in 26% of cases (17% API2-MALT1, 5% IGH-MALT1, 3% IGH-unknown translocation partner, and 1% IGH-BCL10). Aneuploidy was associated with IGH-MALT1 and IGH-BCL10 but only rarely with API2-MALT1. There was striking site specificity, with API2-MALT1 showing a marked predilection for lung and intestine, and IGH-MALT1 and IGH-BCL10 occurring almost exclusively in lung. Twenty-three percent of translocation-negative primary MALT lymphomas from diverse sites showed complete/partial trisomy 18. No MALT lymphomas with translocations involving IGK, IGL, BCL6, or FOXP1 were identified. This FISH panel detected cytogenetic abnormalities in half of all MALT lymphomas, and translocations arose preferentially in MALT lymphomas of the lung and gastrointestinal tract. Differences in incidence and anatomic site specificity of translocations between North American and non-North American cases may reflect geographic variability of infectious or other etiologic factors.