The association between intermediate filaments (IF) and microtubules (MT) has been demonstrated by several experiments using MT inhibitors and by microinjecting specific antibodies. The actin cytoskeleton has recently been assigned a role in this process of drug induced IF collapse. However, this was not found to be true in large cells with irregular morphology. For instance, in early passage diploid fibroblasts of human origin and in armadillo cell lines, where the cells are large, irregular in shape and exhibit prominent stress fibers (SF), depolymerization of MT with nocodazole did not lead to collapse of IF. Instead, the IF formed bundles of coils that seemed to associate with the SF. Disintegration of the SF with cytochalasin B led to the collapse of the IF. It appears that the actin organization in such large cells with extensive SF, is not as contractile as in typical spindle shaped fibroblasts which have relatively less stable actin organization. The stable SF may actually prevent IF collapse.