Large numbers of chemicals of a variety of types exhibit apparent hormetic effect on cultured cancer cells, causing stimulation of cell growth at low doses, followed by inhibition at higher doses1. Its underlying mechanisms and influence on anticancer treatment have not been elucidated yet. Coptis rhizoma, a Chinese medicinal herb, and its major active constituent, berberine (BER), have anticancer properties2. This study aims to investigate the hermetic effects of crude extrat of coptis rizhoma (COP) and BER in vitro and in vivo, and its influence on the anticancer activities of chemotherapeutic agents, including fluorouracil (5-FU), camptothecin (CPT), and paclitaxel (TAX) in B16 murine melanoma cancer cells. B16 cells were treated with a series of doses of COP and BER, combined with 5-FU, CPT, and TAX. Cell viability was measured by an XTT (2,3-bis-(2-methoxy-4- nitro-5-sulfophenyl)-2 H-tetrazolium-5-carboxanilide) assay. The C57BL/6 mice were used for in vivo transplantation tumor model. B16 cells were injected subcutaneously into C57BL/6 mice on Day 0. Mice received COP and berberine in different concentrations by oral gavage on Day 0 and every two days after that. Body weight and tumor size were monitored. Intracellular ROS levels were determined by measuring the oxidative conversion of cell permeable 2′,7′-dichlorofluorescein diacetate to fluorescent dichlorofluorescein. Multidrug resistance (MDR) activity of B16 cells was assessed by rhodamine 123 retention assay. The expression of protein ERK1/2 was determined by Western Blot. Both COP and BER significantly stimulated B16 cell growth at low doses, and inhibited cell growth at higher doses in vitro. Meanwhile, COP significantly exhibited hormetic effect in a transplantation tumor model in C57BL/6 mice, however, BER did not show similar effect in vivo. These phenomenons were consistent to the typical properties of hormesis as evidenced by a two-phases of cell growth curve and the dosage range of COP and BER3. Combinations of COP or BER with chemotherapeutic agents exhibited strong inhibitory effects on the anticancer activities of 5-FU, CPT, and TAX in B16 cells in vitro. Interestingly, COP and BER at low doses significantly reduced cellular ROS production, MDR activity, and increased phospho-ERK1/2 level in B16 cells, suggesting that COP and BER at low doses induced a protective response in cells to stress stimulation, leading to growth enhancement, which exhibited a typical hermetic phenomenon These results provide important information to understand the nature of hormesis, and suggest caution in the clinical application of coptis rhizoma used along or in combination with chemotherapeutic agents in cancer treatment.