It has been recently shown that the combination of peroxisome proliferator-activated receptor (PPAR) γ and retinoid X receptor (RXR) ligands enhances their activity as inducers of differentiation and apoptosis. It has also been demonstrated that the induction of the ubiquitin-dependent degradation of PPARγ/RXR heterodimers by the proteosome is activated upon binding of a receptor ligand. Based on this knowledge, we hypothesized that the use of a proteosome inhibitor may enhance the activity of the receptor ligands by prolonging their activation. For this purpose, we tested the antiproliferative activity of the combination of the proteosome inhibitor, bortezomib with PPARγ and RXR ligands, rosiglitazone, and bexarotene as compared to single agents in a series of cell lines derived from ALK+ (JB6, SUPM2)/ALK- (SKB, MAC1) anaplastic large cell lymphoma (ALCL), Burkitt’s lymphoma (Hs-Sultan) and multiple myeloma (ARH77). In the combination studies, 5 nM bortezomib was added to cell culture 6 h prior to the addition of 10 μM rosiglitazone and/or 25 μM bexarotene. None of the cell lines reached IC50 as assessed by CellTiter 96 Aqueous cell proliferation assay (Promega), and represented as percent of untreated controls, following 72 h incubation with serial concentrations of rosiglitazone (5, 10, 25, 50 μM) or bexarotene (25 and 50 μM). Bortezomib IC50 was reached only in JB6 cells at 5 nM or in MAC1 and SKB cells at 20 nM at 72 h. The IC50s were reached by 5 nM bortezomib/10 μM rosiglitazone in SUPM2 cells or by 5 nM bortezomib/10 μM rosiglitazone/25 μM bexarotene in Hs-Sultan cells at 72 h. Multiple myeloma-derived cells ARH77 showed resistance to single agent bortezomib, rosiglitazone or bexarotene at all the concentrations tested. However, in these cells, IC50 was reached only by the combination of 5 nM bortezomib/10 μM rosiglitazone/25 μM bexarotene at 96 h of incubation. Surprisingly, ALK+ALCL-derived JB6 cells reached their IC50s with any of the drug combinations (5 nM bortezomib/10 μM rosiglitazone; 5 nM bortezomib/25 μM bexarotene; 5 nM bortezomib/10 μM rosiglitazone/25 μM bexarotene) between 24 (5 nM bortezomib/10 μM rosiglitazone/25 μM bexarotene) and 72 h (5 nM bortezomib/10 μM rosiglitazone; 5 nM bortezomib/25 μM bexarotene). After 72 h of incubation, the percentage of JB6 viable cells treated with 5 nM bortezomib/10 μM rosiglitazone/25 μM bexarotene as compared to untreated controls, was significantly lower than the percentage of cells treated with single agent 5 nM bortezomib (22% ±0.6 vs 45% ± 1.4, P<0.05). In conclusion, our data show that bortezomib at the lowest IC50 (5 nM/JB6 cells) enhances the antiproliferative effects of rosiglitazone or bexarotene in JB6, SUPM2 and Hs-Sultan cells. Ultimately, after 96 h of incubation, the addition of 5 nM bortezomib to the combination of 10 μM rosiglitazone/25 μM bexarotene significantly enhances the antiproliferative activity in myeloma-derived ARH77 cells that showed resistance to single agent bortezomib (39% ±3.8 vs 73% ±1.2, P<0.05).