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Background Previously, we have demonstrated that dietary supplementation with resveratrol lowers synovial hyperplasia, inflammatory markers and oxidative damage in an acute antigen-induced arthritis (AIA) model. Objectives In this work, we investigated whether resveratrol can also regulate this abnormal proliferation of synovial tissue in an acute AIA model by inducing cell death pathways and by modifying the angiogenesis in the synovial membrane. Methods Animals were randomly divided into 3 groups: control, AIA, and resveratrol-treated AIA group. Resveratrol (12,5 mg/kg/day) was given orally 8 weeks before AIA induction until sacrifice day (48 h after intra-articular injection). Control and AIA animals were administered 100 μl of water. Resveratrol effects on autophagy and apoptosis were evaluated by LC3 and active caspase-3 expression (confocal and immunohistochemistry, respectively). Angiopoietin 1 (Ang-1), vascular endothelial growth factor (VEGF), and the nuclear factor NF- kappa -B p65 subunit (p65) were also determined by immunohistochemistry and cartilage degradation with Safranin-O. Results Resveratrol significantly reduced the histological score of synovial tissue. Results showed a significant higher expression of LC3 signals in the AIA synovial membranes, compared with control samples, in which the presence of vesicles was easily observed. Interestingly, the synovial tissues from the resveratrol group showed a significantly (p≤0.001) higher signal for LC3, compared with the AIA samples. Active caspase-3 expression was up-regulated at the same level in the synovial membranes of AIA group than in resveratrol-treated AIA group; however, in resveratrol-treated AIA group active caspase-3 signal was mainly located in the inflammatory cells. Resveratrol consumption significantly attenuated Ang-1 signal, whereas expression of VEGF showed a non significant reduction. Resveratrol administration also mitigated, even not significantly, p65 expression that was significantly higher in the AIA animals than those from the control animals. In addition, resveratrol decreased articular cartilage degradation. Conclusions These data suggest that resveratrol is able to modulate synovial hyperplasia by increasing autophagic cell death and limiting angiogenic response in an acute AIA model, which could also modulate the inflammatory and destructive processes for rheumatoid arthritis. Acknowledgements Instituto de Salud Carlos III-Ministerio de Economia y Competitividad N° Expediente PI12/02771. Uniόn Europea-Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” Disclosure of Interest None declared