The aim of this study was to investigate the effect of arsenic trioxide (As(2)O(3)) combined with bortezomib on the proliferation, apoptosis and beta-catenin level in myeloma cell lines. Myeloma cell lines RPMI8226, CZ-1 and NCI-H929 were treated with As(2)O(3) and bortezomib alone or in combination for 48 hours. Trypan blue dye exclusion and modified MTT were used to assess the cell viability. Flow cytometry with Annexin V-FITC and PI staining was used to detect the apoptosis rate. The beta-catenin level was analyzed by Western blot. The results showed that IC(50) of bortezomib to RPMI8226, CZ-1 and NCI-H929 were 46.9, 20.7 and 6.8 nmol/L, respectively. After the combination treatment with bortezomib (5 nmol/L) and As(2)O(3) (1 micromol/L), the cell viability of RPMI8226, CZ-1 and NCI-H929 decreased from 88.99%, 72.23%, 51.06% to 54.01%, 39.59%, 25.00%(p<0.05), the apoptosis rate increased from 11.1+/-0.1%, 26.8+/-1.7%, 46.8+/-5.5% to 36.1+/-2.2%, 60.4+/-3.8%, 76+/-5.6% (p<0.01) respectively. The Q value of two groups lies between enhancement and significant enhancement (1.198 - 3.75). Besides, beta-catenin levels in tested cell lines were decreased to 24.15%, 31.85%, 33.72% of their basic constitutions respectively (p<0.05). It is concluded that combination treatment of As(2)O(3) and bortezomib can enhance the proliferation inhibition and apoptosis induction of bortezomib to myeloma cell lines, reduce beta-catenin level, and increase the sensitivity of myeloma cell lines to bortezomib.