Interactions between interleukin (IL)-8 and its receptors, C-X-C chemokine receptor 1, (CXCR1) and CXCR2 serve crucial roles in increasing cancer progression. Inhibition of this signaling pathway has yielded promising results in a number of human cancers, including breast, melanoma and colon. However, the effects of CXCR1/2 antagonist treatment on pancreatic cancer remain unclear. The present study aimed to demonstrate that treatment with the clinical grade CXCR1/2 antagonist, reparixin, or the newly discovered CXCR1/2 antagonist, SCH527123, may result in a reduction of the malignant features associated with this lethal cancer. The effects of reparixin or SCH527123 exposure on human pancreatic cancer cell lines BxPC-3, HPAC, Capan-1, MIA PaCa-2, and AsPC-1 were examined in regard to cell proliferation, cell viability, colony formation and migration. The effects of CXCR1/2 inhibition on the protein expression of well-known downstream effectors, including phosphorylated (p)-signal transducer and activator of transcription 3 (STAT3), p-RAC- serine/threonine-protein kinase (p-AKT), p-extracellular signal-regulated kinase (p-ERK1/2) and p-ribosomal protein S6 (p-S6), were assessed by western blotting assays. The effects of IL-8 signaling on the proliferative activities intrinsic to the human pancreatic cancer cell lines Capan-1, AsPC-1 and HPAC were examined by bromodeoxyuridine assay. Treatment with either reparixin or SCH527123 yielded dose-dependent growth suppressive effects on HPAC, Capan-1 and AsPC-1 cells that may have otherwise undergone robust proliferation upon IL-8 stimulation. In addition, reparixin or SCH527123 treatment inhibited CXCR1/2-mediated signal transduction, as demonstrated by the decreased phosphorylation levels of effector molecules STAT3, AKT, ERK and S6 that are downstream of the IL-8/CXCR1/2 signaling cascade in HPAC cells. These data were in close agreement with the reduced cell migration and colony formation. Results from the present study suggested that reparixin and SCH527123 may be promising therapeutic agents for the treatment of pancreatic cancer by inhibiting the IL-8/CXCR1/2 signaling cascade.