This study was aimed to investigate the effect of grape seed proanthocyanidin extract (GSPE) on interleukin-17 (IL-17)-induced interleukin-6 (IL-6) production in A549 human pulmonary epithelial cells. Cells were treated with IL-17 (10 ng/ml) or GSPE (50 μg/ml), or both. The effects of GSPE on cell viability and apoptosis were evaluated. The mRNA and protein levels of IL-6 were determined by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Expressions of inhibitory factor κB-α (IκB-α) and ERK 1/2, p38, and JNK mitogen-activated protein kinase (MAPK) were examined by Western blot analysis. GSPE significantly inhibited both GSPE treatment only and IL-17-induced mRNA expressions and protein productions of IL-6 in pulmonary epithelial cells (p < 0.01). GSPE decreased the IL-17-induced phosphorylation of IκB-α. The IL-17 stimulated ERK 1/2, p38, and JNK MAPK activities and GSPE decreased IL-17-stimulated ERK 1/2, p38, and JNK MAPK activities. GSPE also attenuated TNF-α and IL-1β-induced IL-6 productions (p < 0.05). Our results show that GSPE may inhibit IL-17-stimulated IL-6 productions in human pulmonary epithelial cells by inhibiting MAPK and nuclear factor-κB-mediated signaling pathway.