STI571 (formerly CGP57148) and AG957 are small molecule inhibitors of the protein tyrosine kinase (PTK) p145^abland its oncogenic derivative p210^bcr-abl. AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct comparison of these inhibitors has previously been reported, so this study compared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and their p210^bcr-abl-expressing factor-independent derivatives. STI571 was a more potent inhibitor of³H-thymidine incorporation in p210^bcr-abl-expressing cells than was AG957, and it showed superior discrimination between inhibitory effects on parental cell lines and effects on their p210^bcr-abl-expressing derivatives. Assays performed with and without growth factor demonstrated that STI571 but not AG957 reversed the p210^bcr-abl-driven factor independence of cell lines. p210^bcr-abl-expressing cells were less sensitive to AG490 than to AG957 or STI571. However, for p210^bcr-abl-expressing clones from all 3 cell lines, synergistic inhibition was demonstrated between STI571 and concentrations of AG490 with no independent inhibitory effect. Inhibition of nucleic acid synthesis with AG957 treatment was associated with reduced cell numbers, reduced viability, and small pyknotic apoptotic cells. At concentrations of STI571 that reversed the p210^bcr-abl factor-independent phenotype, STI571 treatment and growth factor deprivation together were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) STI571 is a more potent and more selective inhibitor of a p210^bcr-abl-dependent phenotype than AG957; (2) AG490 synergizes with STI571 to enhance its inhibitory effect on p210^bcr-abl-driven proliferation; and (3) the combination of p210^bcr-abl-tyrosine kinase inhibition and growth factor signal withdrawal can be sufficient to induce apoptotic death of transformed cells.