Background: Sequential therapy with MKIs in the management of refractory thyroid cancer cannot be standardized with data coming form randomized clinical trials. Methods: We retrospectively analyzed pts with advanced radioactive-iodine refractory differentiated thyroid cancer (DTC) or unresectable medullary thyroid cancer (MTC) treated with MKIs, from January 2010 to November 2015 included in the Spanish group of rare cancers (GETHI) database. Most used MKIs included sorafenib, lenvatinib, vandetanib, cabozantinib, sunitinib and pazopanib. Primary endpoint was to evaluate the progression-free survival in first-line (PFS1) compared to PFS in second-line (PFS2) independently of the MKIs used in both setting. Secondary objectives were overall survival (OS), overall response rate (RR) and overall safety profile. Results: 74 pts were analyzed (43 DTC, 31 MTC). All pts received MKIs in first-line (1^st) and 43 (58.1%) in second-line (2^nd). Median PFS1 was 11.53 months (CI 95% 11.53-14.5) and median PFS2 was 14.07 months (CI 95% 8.07-20.06) in pts with MTC (p = 0.698). In patients with DTC median PFS1 was 8.66 months (CI 95% 6.74-10.59) and median PFS2 was 5.53 months (CI 95% 3.99-7.06) (p = 0.036). Dose reductions were needed in 66.7% and 40% for 1^st and 2^nd respectively in MTC. In the case DTC, fewer reductions were necessary 41,9% and 21.7%. 64 patients were assessable for efficacy. Overall RR in 1^st of DTC was 47%, stable disease (SD) was 38,2% and 14.7% had progressive disease (PD); in the 2^nd RR was 25%, SD was 35% and PD was 40%. In MTC, RR were 39,2% and 27.8%, SD were 50% and 50%, PD were 10.5% and 22.2; for 1^st and 2^ndrespectively. Median OS in MTC (27 months [CI95% 18.8-35.1]) was significantly longer compared with DTC (15.43 months [CI95% 6.64-24.22] p = 0.05). Conclusions: The use of MKIs in different treatment lines in DTC and MTC is a common approach in routine clinical practice even the lack of randomized clinical trials that support this strategy. However, signals of activity could be observed with sequential therapies in retrospective series in these orphan tumors that warrants further prospective trials to demonstrate improvements in survival.