Purpose A high percentage of early-stage, high-grade gastric mucosa-associated lymphoid tissue (MALT) lymphomas remain Helicobacter pylon dependent. t(11;18)(q21;q21), a genetic aberration highly predictive of H pylori-independent status in low-grade gastric MALT lymphoma, is rarely detected in its high-grade counterpart. This study examined whether nuclear expression of BCL10 or nuclear factor kappa B (NF-kappaB) is useful in predicting H pylori-independent status in patients with stage IE high-grade gastric MALT lymphomas. Patients and Methods Twenty-two patients who had participated in a prospective study of H pylon eradication for stage IE high-grade gastric MALT lymphomas were studied. The expression of BCL10 and NF-kappaB in pretreatment paraffin-embedded lymphoma tissues was evaluated by immunohistochemistry and confocal immunofluorescence microscopy. The presence of t(11;18)(q21;q21) was identified by a multiplex reverse transcriptase polymerase chain reaction of the API2-MALT1 chimeric transcript. Results Aberrant nuclear expression of BCL10 was detected in seven (87.5%) of eight H pylori-independent and in none of 14 H pylori-dependent high-grade gastric MALT lymphomas (P < .001). All seven patients with nuclear BCL10 expression had nuclear expression of NF-kappaB, compared with only two of 15 patients without nuclear BCL10 expression (P = .002). As a single variable, the frequency of nuclear expression of NF-kappaB was also significantly higher in H pylori-independent tumors than in H pylori-dependent tumors (seven of eight [87.5%] v two of 15 [12.3%]; P = .002). The API2-MALT1 fusion transcript was detected in only one (12.5%) of eight H pylori-independent lymphomas. Conclusion Nuclear expression of BCL10 or NF-kappaB is highly predictive of H pylori-independent status in high-grade gastric MALT lymphoma, and coexpression of these two markers in the nuclei is frequent.