The relationship between the nuclear morphology and the microtubular organization of L 1 0 0 and L 1 0 0 0 cells, two vincristine-induced multidrug resistant human acute lymphocytic leukemia cell lines, was examined and compared to that L 0 parental cells. The L 0 parental cells contained a round nucleus and the microtubules were evenly distributed throughout the cytoplasm. In contrast, the microtubules of the L 1 0 0 and L 1 0 0 0 cells were localized between the lobular structures of a multilobulated nucleus. Disassembly of microtubules in L 1 0 0 and L 1 0 0 0 cells by colchicine resulted in the loss of the multilobulated morphology of the nucleus. While the total cellular content of tubulin of L 0 and L 1 0 0 cells was similar, the content of microtubules of L 1 0 0 cells was only 55% of that observed in L 0 cells. Two, 28 kDa (pI 6.9) and 31 kDa (pI 4.4), microtubule-associated proteins were found to be overexpressed in L 1 0 0 and L 1 0 0 0 cells. The results indicate that the multilobulated nuclear morphology of L 1 0 0 and L 1 0 0 0 cells is dependent upon the unique and intact organization of the microtubules; the distinct organization of the microtubules and the multilobular nuclear morphology of the two resistant cell lines may be due to the differential expression of specific microtubule-associated proteins.