In cultures of KNS-62 cells derived from a human lung squamous cell carcinoma, the initial growth arrest in the continuous presence of interferon-gamma (IFN-gamma) turned to cytopathic effects after 2 days of treatment. The remaining viable cells showed grossly distorted morphology, with enlargement and extensions up to 5 cell diameters. The presence of apoptotic cells was shown 3 days after treatment with IFN-gamma. Immunocytochemically, the microtubular structures appeared augmented and highly aggregated. The level of alpha-tubulin-specific mRNA was distinctly increased after administration of IFN-gamma, and the amount of extractable alpha-tubulin protein was reduced. In parallel kinetics experiments, growth arrest by serum depletion or by contact inhibition during confluence resulted in reduced levels of alpha-tubulin-specific mRNA and in slightly elevated alpha-tubulin protein. The IFN-gamma-induced effects suggest interference with assembly or maintenance of the tubulin cable network, presumably associated with cell deformation and cytotoxicity.