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Simple Summary Changes in glycosylation, such as incomplete synthesis and higher density of O-glycans on the cell surface, are frequently observed in cancer cells. Several types of truncated O-glycan structures, e.g., T/Tn antigens, are suspected to disrupt molecular interactions between tumor microenvironment and immune cells, for instance, facilitating cancer immune-escape. Therefore, numerous exogenous lectins targeting aberrant O-glycans are interesting tools for cancer diagnosis, prognosis, and therapy. However, the ability of exolectins to detect subtle alterations in the glycome of tumor cells and to interfere in tumor/healthy cell interactions remains largely unknown. The present article reports for the first time that the Helix pomatia (HPA) lectin, a well-known T/Tn-specific lectin, currently used as a tool in cancer diagnostics, kills Tn-positive leukemia cells and Tn-negative lymphoma cells but does not affect healthy lymphocytes. Thus, HPA could be used to discriminate between tumor and healthy cells, and detect subtle alterations in the glycosylation profile. Abstract Morniga G is a T/Tn-specific lectin, inducing cell death in Tn-positive leukemias but not in healthy lymphocytes. Helix pomatia lectin (HPA) is another T/Tn-specific lectin, currently used as tool for cancer diagnostics. The HPA-mediated tumor cell death was evaluated on human leukemia and mouse lymphoma cells, and compared to the effect of Morniga G. Both lectins induced an equivalent percentage of cell death in Tn-positive Jurkat human leukemia. In contrast, EL4 mouse lymphoma resisted Morniga G-mediated cytotoxicity but were killed by HPA at concentrations of 2.5 μg/mL (0.032 nM) and higher. In both malignant cells, HPA-mediated cell death showed features compatible with apoptosis (annexin-externalization, caspase-activation, mitochondrial membrane depolarization, and ROS production). Cytometry analysis indicated that EL4 cells are T/Tn-negative. Because previous results showed a high amount of N-acetylgalactosamine (GalNAc, sugar present in Tn antigen) on EL4 cell surface, this GalNAc could be involved in the formation of truncated O-glycans other than the T/Tn residues. When compared to Morniga G, bioinformatic analysis suggested that HPA benefits from an extended carbohydrate-binding site, better adapted than Morniga G to the accommodation of more complex branched and truncated O-glycans (such as core 2). Finally, HPA killed EL4 cells but not healthy lymphocytes in a mixture of lymphoma cells + lymphocytes, suggesting that HPA selectively triggers tumor cell death.