The cell density-dependent growth inhibition of human SK-N-MC neuroblastoma cells is initiated by increased ganglioside sialidase activity leading to elevated cell surface presentation of ganglioside GM1, a ligand of galectin-1. We herein show that the extent of the galectin`s cell surface expression coincides with marked increases of the sialidase activity. RT-PCR analysis excludes a regulation on the transcriptional level. Exposure of cells to purified galectin-1 reveals its carbohydrate-dependent activity to reduce cell proliferation. Assays to detect DNA fragmentation biochemically and cytometrically and to block caspases render it unlikely that galectin-1 acts as classical proapoptotic factor on these cells. Since the chimeric galectin-3 shares binding sites and binding parameters with galectin-1 for these cells, we tested whether this galectin will elicit the same response as the homodimeric crosslinking galectin-1. Evidently, galectin-3 fails to affect cell growth by itself but interferes with galectin-1 upon coincubation. Its proteolytically truncated variant, the C-terminal lectin domain with impaired capacity to form aggregates when surface bound, has only weak binding properties. Thus, the way how the galectin-1 relative to galectin-3 interacts topologically with an apparently common set of ligands is crucial for eliciting post-binding events. We conclude that galectin-1 is a probable effector in the sialidase-dependent growth control in this system. Moreover, the experiments with galectin-3 reveal functional divergence, most probably based on different topologies of presentation of homologous carbohydrate-binding sites.