Agglutination of S49 mouse lymphoma cells by Ricinus communis I agglutinin can be reversed by the competing haptenic saccharide, lactose, soon after agglutination, but after further incubation in the absence of lectin the agglutination reaction could not be reversed by lactose and the cells remained as multicell aggregates. The irreversibility of S49 cell agglutination was time, temperature and lectin concentration dependent and its onset correlated with ultrastructurally observed deformation of adjacent cell surfaces and an increase in the proportion of adjacent cell surface areas in close apposition within multicell aggregates. Pretreatment of S49 cells with cytochalasin B or cytochalasin B plus vinblastine enhanced R. communis I agglutinin-mediated agglutination, while vinblastine alone and fluoride plus azide had essentially no effect. When drug-treated cells were agglutinated and then incubated in lectin-free drug-containing media for various times prior to lactose addition, the drug effects were more pronounced. Cytochalasin B alone or with vinblastine inhibited lactose reversal of S49 cell agglutination compared to the drug-free controls, while fluoride plus azide enhanced hapten reversibility. Electron microscopic analysis revealed that the onset of agglutination irreversibility correlated with cell surface deformation in the drug-treated cells. Cell aggregates that were more readily reversible by lactose (fluoride plus azide) were unchanged or less deformed, while S49 aggregates treated with cytochalasin B plus vinblastine were more deformed compared to controls without drugs. These experiments suggest a role for cell surface deformability as an important secondary effect during lectin-mediated cell agglutination of S49 lymphoma cells.