Osteoarthritis (OA) is the most common musculoskeletal joint disease worldwide [1] and one of the major causes of chronic pain [2]. Treatment of pain associated with OA is still suboptimal [3]. Vascular endothelial growth factor-A165b (VEGF-A165b) is an anti-angiogenic isoform of VEGF-A [4], which has anti-nociceptive effects in models of diabetic neuropathy [4] and inflammatory arthritis [5]. This study tested the hypothesis that VEGF-A165b can reverse enhanced pain behaviour in the monosodium iodoacetate (MIA) model of OA in rats. Male Wistar rats (n=32, 200-250g) were used in this study. Animals were either injected with MIA (1 mg/50 µl saline, n=23) intra-articularly in the right knee under brief anaesthesia (isofluorane 2-3% in O2) or received no injection (n=9). Using a cross-over design, rats were then given: VEGF-A165b (20 ng/g body weight, days 0-14) followed by PBS vehicle (days 15-28 “MIA/VEGF14”, twice weekly intra-peritoneal (I.P.)), or PBS (days 0-14) followed by VEGF-A165b (days 15-28 I.P., “MIA/VEGF28”). Controls were MIA/PBS (days 0-28, I.P.) or naïve untreated. Mechanical withdrawal threshold to von Frey filaments and weight bearing asymmetry by incapacitance meter were determined twice weekly. On day 28, rats were sacrificed with an overdose of pentobarbital (100 mg I.P.). MIA/VEGF14 rats showed a significant reduction in weight bearing asymmetry compared to MIA/PBS rats on days 18, 25 and 28. The percentage of weight borne on ipsilateral hindpaw in the MIA/VEGF14 rats vs. MIA/PBS group was 46.48 ± 1.68 vs 41.16 ± 2.15% on day 18 (2 way ANOVA with post-hoc Tukey’s tests, p<0.05), 44.74 ± 2.66 vs. 38.62 ± 2.68% on day 25 (p<0.05) and 45.46 ± 1.86 vs. 36.59 ± 2.17% on day 28 (p<0.001). Treatment of MIA rats with VEGF-A165b on days 0-14 also returned mechanical von Frey (vF) withdrawal threshold levels to control levels. Mechanical withdrawal threshold in MIA/VEGF14 group vs. naïve/PBS group was 9.71 ± 1.14 vs. 9.63 ± 1.57 g on day 25 and 8.46 ± 1.16 vs. 9.94 ± 2.30 g at the end of the study. (Data expressed as mean ± SEM). Weight bearing and vF thresholds in MIA/VEGF28 rats were not different from those of MIA/PBS rats. These results indicate that VEGF-A165b has an anti-nociceptive effect in the MIA model of OA in rat when given early, but not later, in development of the arthritis.