The aim of the present study was to evaluate clinical activity, and the pharmacodynamic and pharmacokinetic profiles, of oral metronomic vinorelbine (VNR) plus dexamethasone (DEX) in metastatic castration-resistant prostate cancer (mCRPC) patients. Fourty-one patients (92 % chemotherapy-resistant) received 30 mg/day VNR p.o. thrice a week plus 1 mg/day DEX p.o. until disease progression. Plasma soluble B cell antigen 7 homolog 3 (sB7-H3), vascular endothelial growth factor (VEGF), and thrombospondin-1 (TSP-1), were measured by ELISA. Plasma VNR was detected using a LC-MS-MS system. The fraction of patients free of progression, defined by criteria of the Prostate Cancer Clinical Trials Working Group 2, at 3 months was 61 %. PSA decrease ≥50 % from baseline was observed in 35 % of patients. Median PFS and OS were 4 months (95 % CI, 2.8-6.9) and 17.5 months (95 % CI, 10.8-24.5), respectively. Toxicity was mild, and no grade 4 toxicities were found. The mean plasma VNR Cmax ranged from 1 to 2.7 ng/ml (Tmax 1.1 h) and no evidence of drug accumulation was found. A moderate relationship was found between plasma sB7-H3 and PSA values (r = 0.565; P = 0.0094) at the baseline. Increased PFS (11.3 vs. 2.8 months; P = 0.0298) was observed in patients with sB7-H3 levels <30.25 ng/mL. Plasma VEGF AUC0-24day increased in non-responders (P < 0.0001), whereas responders maintained higher plasma TSP-1 AUC0-24day (P = 0.0063). In conclusion, metronomic VNR plus DEX showed favourable activity, and a low toxicity profile, in mCRPC patients. Plasma sB7-H3, VEGF and TSP-1 levels are potential pharmacodynamic markers at the reached low plasma concentrations of vinorelbine metronomically administered.