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Background: The aim of this study was to validate in 20-year follow-up (FU) the outcomes reported in World J Surg 2010; 34(6):1232-8 on recurrent nodular goiter in the contralateral thyroid lobe among patients after thyroid lobectomy (TL) for multinodular goiter (MNG) receiving versus not receiving postoperative prophylactic levothyroxine (LT4) treatment., Methods: Some 150 consenting patients underwent TL for MNG in 2000-2003. They were randomized to two groups, 75 patients each: (a) receiving prophylactic LT4 treatment postoperatively (dose range 75-125 microg/day to maintain thyroid-stimulating hormone values within 0.27-1.0 mU/L), and (b) not receiving LT4. Sixty-month FU was extended to 240 months for all the consenting patients. The primary outcome was prevalence of recurrent goiter. The secondary outcome was re-intervention rate for recurrent goiter. The outcomes were stratified according to individual iodine metabolism status assessed by urinary iodine excretion., Results: During the 5-year FU (5 patients were lost) recurrent goiter was found in patients receiving versus not receiving LT4 in 1.4% versus 16.7% (p = 0.001) whereas during 20-year FU (29 patients were lost) it was 3.3% versus 30.0% of patients, respectively (p = 0.031). During 20-year FU 4.9% versus 30.0%, respectively, of patients receiving versus not receiving LT4 required contralateral thyroid lobe treatment/surgery (p = 0.028). LT4 decreased recurrence rate among iodine-deficient patients (10.0% vs. 70.0%, respectively; p = 0.037) but not among iodine-sufficient patients (0.0% vs. 10.0%, respectively; p = 0.056)., Conclusions: Twenty-year FU data confirmed that prophylactic LT4 treatment significantly decreased the recurrence of nodular goiter and the need for completion intervention/surgery, mostly among patients with iodine deficiency., (© 2024 International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)