DUSP28, a member of the atypical dual‑specificity phosphatase (DUSP) family, is a candidate tumor-related gene in hepatocellular carcinoma (HCC) selected by genome‑wide approach, but its pathological role in HCC has not been elucidated. Here, we report for the first time that DUSP28 is involved in HCC progression. Quantitative real‑time PCR and semi‑quantitative RT-PCR showed notably elevated expression of DUSP28 in HCC specimens compared to that in corresponding adjacent non‑tumor liver. DUSP28 overexpression promoted HCC cell proliferation, colony formation and soft agar colony formation in vitro while DUSP28 knockdown resulted in the opposite effects. Furthermore, the flow cytometric analysis indicated that DUSP28 could lead to an increased population of cancer cells in S phase, with a concomitant decrease of cells in G1 phase. Investigation of the mechanism revealed that DUSP28 could activate the p38 mitogen-activated protein kinase (MAPK) signaling pathway. Taken together, these data demonstrate that DUSP28 plays a significant role in HCC progression and may be a feasible molecular target for anti-cancer therapy.