A deoxycytidine kinase-deficient variant of HL60 cells (HL60-araC), isolated by its resistance to 1-beta-D-arabinofuranosyl cytosine (ara-C), shows cross-resistance to the differentiation-inducing and growth-inhibitory effects of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). This is not due to the lack of uptake of 1,25(OH)2D3 by HL60-araC cells, shown by an increased rate of intracellular accumulation of [3H]-1,25(OH)2D3, or to the lack of expression of the gene for the vitamin D3 receptor. However, down-modulation of the expression of this gene by 1,25(OH)2D3 is markedly delayed in HL60-araC cells, and the down-regulation of the expression of the c-myc gene is also delayed. In contrast, the expression of the constitutively expressed 16S mitochondrial rRNA gene is unchanged by 1,25(OH)2D3 treatment of either cell subline. These findings suggest that some cases of drug resistance may be associated with defective functioning of a differentiation pathway.