We aimed to conduct a systematic review and metaanalysis of studies reporting the performance of radioactive iodine (I) therapy in differentiated thyroid cancer (DTC) patients requiring a completion treatment after lobectomy. We also evaluated the response to I therapy according to 2015 American Thyroid Association guidelines and the adverse events. A specific search strategy was designed to find articles evaluating the use of I in patients with evidence of DTC after lobectomy. PubMed, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science were searched. The search was updated until January 2020, without language restriction. Data were cross-checked and any discrepancy discussed. A proportion metaanalysis (with 95% confidence interval) was performed using the random-effects model. Metaregressions on I success were attempted. The pooled success ablation rate was 69%, with better results in patients receiving a single administration of about 3.7 GBq; high heterogeneity was found (I test, 85%), and publication bias was absent (Egger test, = 0.57). Incomplete structural responses were recorded in only 14 of 695 (2%) patients enrolled in our analysis. Incomplete biochemical responses were observed in 8%-24% of patients, with higher rates (24%) in patients receiving low radioiodine activities (∼1.1 GBq) and lower rates (8%-18%) in patients receiving higher activities of radioiodine (∼3.7 GBq). Neck pain due to thyroiditis was reported in up to 18% of patients, but in most cases, symptoms resolved after oral paracetamol or a short course of prednisone. Lobar ablation with I is effective, especially when high I activities are used. However, the rate of incomplete biochemical response to initial treatment appears to be slightly higher than in the classic scheme of initial treatment of DTC. Radioisotopic lobectomy should be considered for patients with low- to intermediate-risk DTC requiring completion treatment after lobectomy due to specific individual risk factors or patient preferences.