The aim of this present work was to investigate whether curcumin reverses the adriamycin-resistance of thermotolerant hepatocarcinoma cell line and the underlying mechanisms. Cytotoxicity was evaluated by MTT assay. Apoptosis was determined by flow cytometer using propidium iodide staining. The accumulation of intracellular adriamycin was measured by high-performance liquid chromatography. The expressions of P-glycoprotein (P-gp), heat shock protein 70 (Hsp70), and caspase-3 were analyzed by Western blotting. The thermotolerant hepatocarcinoma cell line HepG2/TT was resistant to adriamycin-induced cytotoxicity and apoptosis. Curcumin, at 5 μmol/L, 10 μmol/L, and 20 μmol/L, decreased the IC₅₀ of adriamycin to thermotolerant HepG2/TT cells and enhanced adriamycin-induced apoptosis in HepG2/TT cells in a concentration-dependent manner. The levels of P-gp and Hsp70 in HepG2/TT cells were obviously higher than that in HepG2 cells. Treatment with curcumin (10 μmol/L) for 24 h significantly reduced the levels of P-gp and Hsp70 in HepG2/TT cells. The accumulation of intracellular adriamycin in HepG2/TT cells was markedly lower than that in HepG2 cells and curcumin (10 μmol/L for 3 h) significantly increased the level of intracellular adriamycin accumulation in HepG2/TT cells. HepG2/TT cells obviously inhibited caspase-3 activation triggered by adriamycin, but co-treatment with 10 μmol/L of curcumin for 24 h significantly augmented the activation of caspase-3 in HepG2/TT cells treated with adriamycin. Curcumin overcomes the adriamycin-resistance of thermotolerant HepG2/TT cells by promoting adriamycin-triggered caspase-3 activation through down-regulating the activity and expression of P-gp and the expression of Hsp70.