Background: Multikinase inhibitors (MKI) have demonstrated significant activity in advanced thyroid cancer. Axitinib is a potent oral MKI targeting the three known receptors of VEGF. Methods: Patients (pts) with advanced RAI-refractory DTC or unresectable MTC in documented disease progression were included in a compassionate use program of axitinib 5 mg bid. Primary end point was response rate (RR) by RECIST, and secondary objectives included progression-free survival (PFS), toxicity profile and biomarker correlation analysis. The program was validated by regulatory authorities and all patients signed informed consent form. Results: 41 pts were enrolled (med age: 54; male: 51%; 29 DTC, 12 MTC). Axitinib was first-line MKI therapy in 39%, second-line in 36% and 24% in subsequent lines. One level dose reduction (5 mg qd) was required in 24% of pts to manage toxicity. Main side effects were grade 1-2, including fatigue (46%), mucositis (24%), diarrhea (24%) and hypertension (19%). Grade 3-4 side effects included anorexia, diarrhea and cardiac toxicity in less than 5% of pts. 32 pts were evaluable for efficacy. In DTC, RR was 41%, stable disease (SD) 18% and progression disease (PD) 41%. In MTC, RR was 30%, SD 40% and PD 30%. Regarding treatment lines, RR in first-line was 69% and SD 31%; in second and third-lines, RR was 20%, SD 30% and PD 50% (p<0.05). No differences in median PFS were observed between DTC and MTC (p=0.509). However, significant differences were found regarding treatment lines: first-line 12.6 months, second-line 8.6 months and successive lines 3.9 months. 15 pts were evaluated for biochemical response. The Kappa index correlation observed between biomarker reduction >30% and tumor growth control (RR + SD) was for thyroglobulin 0.21 (0.30-0.72), CEA 0.22 (0.19-0.64) and calcitonin 0.087 (-0.62-0.79). No correlation was observed in this small number of pts. Conclusions: Axitinib has showed meaningful activity and a safety toxicity profile in refractory and progressive thyroid cancer regardless tumor histology in first and second-line therapy. Efficacy significantly decreases in successive lines suggesting cumulative resistance to MKIs.