In this study, we have characterized infiltrating T lymphocytes from 13 low-grade and 17 high-grade primary gastric MALT lymphomas by immunohistochemistry, with particular regard to the presence, activation, and topographic distribution of cytotoxic effectors. Although the prevalence of CD4+ and CD8+ cells was similar in low- and high-grade lymphomas, higher numbers of TIA-1+ cytotoxic effectors were found in this latter group of cases (11.6 versus 7. 8%; P = 0.004). Activation of CD8+ cytotoxic T lymphocytes (CTLs) was significantly more pronounced in high- than in low-grade lymphomas, as shown by immunostaining for perforin (8.7 versus 4.0%; P = 0.001) and granzyme-B (GrB) (8.7% versus 3.0%; P < 0.0001). Of note, CD20/GrB double labeling showed that high-grade lymphomas carried a markedly higher content (about ninefold) of activated CTLs relative to the number of CD20+ lymphoma B cells (0.081 +/- 0.076 versus 0.009 +/- 0.011; P < 0.0001). Moreover, high-grade lymphomas showed significantly increased apoptotic rates compared to low-grade cases (5.3 and 1.1% of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, respectively; P < 0.0001). In the whole series, the percentage of GrB+ cells and the GrB+/CD20+ ratio showed a strong linear correlation with the number of TUNEL-labeled cells. These findings, together with the frequent colocalization of CTLs and TUNEL+ neoplastic cells, suggested that apoptotic death of lymphoma cells may be due at least in part to the killing by cytotoxic effectors. Our results are consistent with the occurrence of host antitumor cell-mediated immune responses in gastric MALT lymphomas. Moreover, the finding of stronger cytotoxic responses in high- than in low-grade cases is of potential usefulness in the design of more effective therapeutic strategies for the management of these disorders.