Small interfering RNAs (siRNAs) are valuable reagents for efficient gene silencing in a sequence‑specific manner via the RNA interference (RNAi) pathway. The current synthetic siRNA structure consists of symmetrical duplexes of 19‑21 base pairs (bp) with 2 nucleotide (nt) 3' overhangs. In this study, we report that an asymmetric siRNA (asiRNA) consisting of 17 bp duplex region (17 bp asiRNA) exhibited potent activity in inhibiting bcl-2 gene expression and cancer cell proliferation in vitro. Importantly, this asiRNA structure significantly reduced off‑target silencing by the sense strand. To improve the stability of the 17 bp asiRNA, we synthesized a series of chemically modified 17 bp asiRNAs. Further experiments showed that in comparison with the 17 bp asiRNA, the 17 bp asiRNA‑M2, one of the modified 17 bp asiRNAs, exhibited a comparable gene silencing activity and an improved stability in vitro. Furthermore, the 17 bp asiRNA‑M2 with a proteolipid micelle delivery system can effectively suppress the growth of H22 and BGC 803 tumors in vivo. These results suggest that the chemically modified asiRNAs may have potential as an effective therapeutic approach for cancer gene therapy in the future.