Acute promyelocytic leukemia (APL) is associated with chromosomal translocations always involving the RAR alpha gene, which variably fuses to one of several distinct loci, including PML or PLZF (X genes) in t(15;17) or t(11;17), respectively. APL in patients harboring t(15;17) responds well to retinoic acid (RA) treatment and chemotherapy, whereas t(11:17) APL responds poorly to both treatments, thus defining a distinct syndrome. Here, we show that RA, As2O3, and RA + As2O3 prolonged survival in either leukemic PML-RAR alpha transgenic mice or nude mice transplanted with PML-RAR alpha leukemic cells. RA + As2O3 prolonged survival compared with treatment with either drug alone. In contrast, neither in PLZF-RAR alpha transgenic mice nor in nude mice transplanted with PLZF-RAR alpha cells did any of the three regimens induce complete disease remission. Unexpectedly, therapeutic doses of RA and RA + As2O3 can induce, both in vivo and in vitro, the degradation of either PML-RAR alpha or PLZF-RAR alpha proteins, suggesting that the maintenance of the leukemic phenotype depends on the continuous presence of the former, but not the latter. Our findings lead to three major conclusions with relevant therapeutic implications: (i) the X-RAR alpha oncoprotein directly determines response to treatment and plays a distinct role in the maintenance of the malignant phenotype; (ii) As2O3 and/or As2O3 + RA combination may be beneficial for the treatment of t(15;17) APL but not for t(11;17) APL; and (iii) therapeutic strategies aimed solely at degrading the X-RAR alpha oncoprotein may not be effective in t(11;17) APL.