OBJECTIVES:  Comparison of efficacy and safety profile of lenvatinib and sorafenib in the treatment of adult patients with advanced radioactive-iodine-refractory differentiated thyroid cancer (RR-DTC). METHODS:  We performed a systematic review of medical databases (Medline, Embase, Cochrane) in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines to collect all eligible clinical trials referring to the topic of our analysis; the applied limits included human subjects and English language. Predefined outcomes of interest were: overall survival (OS), progression-free survival (PFS), and safety profile; we calculated HR and for dichotomous data: OR for ITT population. Due to the lack of direct clinical trials comparing the drugs we used an adjusted indirect comparison of efficacy and safety of tyrosine kinase inhibitors (TKIs) by Bucher method. RESULTS:  Two completed randomized, placebo-controlled trials met the predefined inclusion criteria: phase 3 trial of lenvatinib in patients with RR-DTC (SELECT; ClinicalTrials.gov Identifier: NCT01321554) and phase 3 trial of sorafenib (DECISION; ClinicalTrials.gov Identifier: NCT00984282). Regarding the primary efficacy outcome, lenvatinib was significantly more effective than sorafenib in respect of PFS improvement (HR=0.36;95%CI: 0.26 – 0.52). The indirect comparison indicated no statistically significant differences the lenvatinib and sorafenib in overall survival, considering data from interim analyses in both trials (HR=0.91;95%CI: 0.53 – 1.58). Similar risk of overall adverse events (OR=2.55; 95% 0.59-11.57) was detected however lenvatinib compared to sorafenib statistically significantly increased the risk for the occurrence of any grade hypertension and lenvatinib treatment was associated with statistically significant reduction in the risk of alopecia when compared with sorafenib. CONCLUSIONS:  Lenvatinib and sorafenib are drugs with strong evidence on efficacy in treatment of RR-DTCBased on the currently available clinical data lenvatinib occurred more efficacious then sorafenib in RR-DTC therapy. Safety profile of the drugs was similar