OBJECTIVES: To collate evidence from published studies evaluating the efficacy and safety of treatments for patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). METHODS: A literature search was conducted in Embase^®, Cochrane, MEDLINE^® and MEDLINE In-Process to identify evidence published from inception until 2018. Grey literature including conference proceedings, heath technology assessments and trial registry websites were searched for relevant studies. The studies were assessed for eligibility against pre-defined inclusion criteria: English language, pharmacological intervention, non-randomised clinical and observational studies. RESULTS: Eighty-two unique studies (44 clinical; 38 observational) were included. Of these, 75 studies have non-comparative study design (43 clinical; 32 observational). The majority of clinical studies were Phase II trials (33), while two were Phase I trials; however, nine did not report the study phase. A majority of the studies (66) included tyrosine kinase inhibitors (TKIs) – sorafenib (19), lenvatinib (15), sunitinib (6), apatinib (4), selumetinib (2), and others/multiple TKIs (20). Among the majority (27) of the TKIs studies reporting objective response rates (ORR), response varied from 10.0% on axitinib to 69.0% on lenvatinib. One study reported no response among patients receiving bortezomib. The median overall survival (OS) varied from 12.7 months with sorafenib to 55.7 months with sunitinib. The ORR in the sorafenib and lenvatinib studies varied from 14.0%–62.5% and 50.0%–69.0%, respectively. The median OS varied from 12.7–36.6 months in sorafenib and 19.9–31.8 months across lenvatinib treated patients, respectively. The safety profile of TKIs indicates that >80.0% of patients had any grade adverse events (AEs), while 19.3%–35.0% had Grade ≥3 AEs. Major AEs across sorafenib recipients were hand–foot skin reactions and weight loss, whereas it was hypertension and appetite loss in lenvatinib treated patients.CONCLUSIONS: RR-DTC patients are frequently treated with TKIs in routine clinical practice. Lenvatinib has demonstrated promising results for the treatment of RR-DTC.