As a well‑known angiogenic factor in different histology and pathological conditions, the pro‑progressive role of vasohibin2 (VASH2) has been reported in various types of tumors. However, its role in drug resistance of breast cancer has not been reported so far. The present study demonstrated that MCF‑7 cells with increased expression of VASH2 demonstrate stronger adriamycin (ADM) resistance compared with MDA‑MB‑231 cells with decreased expression of VASH2. Overexpression of VASH2 in MDA‑MB‑231 cells increased ADM resistance and silencing VASH2 in MCF‑7 cells inhibited ADM resistance. Furthermore, in newly established ADM resistant cell lines, VASH2 was significantly upregulated. These results revealed the promotive role of VASH2 in the ADM resistance of breast cancer cells. In addition, overexpression of VASH2 in MDA‑MB‑231 cells significantly upregulated ATP‑binding cassette sub‑family G member 2 (ABCG2), however silencing VASH2 in MCF‑7 cells inhibited ABCG2 significantly. Silencing ABCG2 abrogated increase of ADM resistance induced by VASH2 overexpression in MDA‑MB‑231 cells. This proved that VASH2 induced ADM resistance through promoting expression of ABCG2, at least in part. Further study regarding the underlying molecular mechanism demonstrated that VASH2 promoted ABCG2 via the protein kinase B (AKT) signaling pathway. Overall, VASH2 may promote drug resistance of breast cancer cells through regulating ABCG2 via the AKT signaling pathway. This suggests a novel therapeutic target to inhibit drug resistance in breast cancer, for a more efficient therapeutic outcome.