BACKGROUND Upregulation of the Wnt/ß-catenin pathway has been demonstrated to promote tumor proliferation and chemoresistance in lymphoma. Our objective was to evaluate the effect of the Wnt/ß-catenin pathway inhibitor WNT974 in lymphoma cells. MATERIAL AND METHODS Human lymphoma cell lines HUT-78 and BJAB were treated with or without 1 μM WNT974±0.15 μg/L doxorubicin (Dox). Cell viability and proliferation were evaluated by CCK-8 and colony formation assay. Expression of proliferating cell nuclear antigen (PCNA), KI67, and apoptotic-related proteins including Bcl-2, Bax, cleaved-caspase3, and cleaved-caspase9, together with Wnt pathway proteins Wnt, ß-catenin, Axin2, and c-Myc, were detected by Western blot analysis. Flow cytometry was used to calculate the ratio of apoptotic cells. RESULTS In HUT-78 and BJAB cells, 1 μM WNT974 significantly reduced viability and colony formation. The expression of 2 markers of tumor cell proliferation, protein PCNA and KI67, was also reduced by WNT974. Treatment with 1 μM WNT974 for 48 h increased the rate of cell apoptosis, inhibited the expression of anti-apoptotic protein Bcl-2, and enhanced pro-apoptotic proteins Bax, cleaved-caspase3, and cleaved-caspase9 expression in both cell lines. After treatment with WNT974 plus Dox, cell viability was markedly decreased compared with Dox treatment alone. Mechanistically, WNT974 prevented the expression of Wnt, Axin2, ß-catenin, and its target gene c-Myc. CONCLUSIONS WNT974 effectively treats lymphoma by inhibiting cell proliferation, inducing cell apoptosis, and enhancing chemosensitivity to Dox, and these effects are dependent on blocking Wnt/ß-catenin signaling.