The commercial preparation named “Tripterygium glycosides” prepared by column chromatography has been used for the treatment of inflammatory and autoimmune diseases with significant efficacy but concurrent toxicity. The aim of this study was to reduce the toxicity of Tripterygium extracts, using cytotoxicity and anti-inflammatory activity of the three principal active components of Tripterygium wilfordii Hook. F. (TWHF)as guiding parameters. Column chromatography was replaced by sodium carbonate extraction for removing the acidic compounds and enriching epoxyditerpenoids and alkaloids in the extract. Results showed that the therapeutic index (IC50/EC50) on murine macrophage Raw 264.7 cells and rat mesangial HBZY-1 cells of the extract prepared by sodium carbonate extraction was significantly higher than that of Tripterygium glycosides(0.8 and 5.2 vs. 0.3 and 2.6, p < 0.05), while its cytotoxicity on human liver HL7702 cells was significantly lower (14.5 ± 1.4 vs. 6.8 ± 0.9, p < 0.05). Further acute oral toxicity experiments showed that the LD50 value of this extract was 1,210 mg/kg compared to 257 mg/kg for Tripterygium glycosides. All the above results suggest that Tripterygium extract prepared by sodium carbonate extraction may represent a potentially optimal source of medicine with good therapeutic index.