OBJECTIVE We investigated the incidence and risk factors of hypothyroidism after thyroid lobectomy, and evaluated the possibility to predict hypothyroidism preoperatively with serologic markers, such as thyrotropin (TSH), thyroglobulin (TG), anti-thyroglobulin (ATA), and anti-microsomal antibody (AMA). METHODS We enrolled 123 consecutive patients who underwent thyroid lobectomy due to benign conditions between May 2004 and April 2008. Only preoperative euthyroid patients were included. Patients were divided into two groups by postoperative thyroid function outcomes, into hypothyroid (n = 97) and euthyroid groups (n = 26), and analyzed specially for the preoperative levels of TSH, TG, ATA, and AMA. RESULTS Twenty-six (21.1%) patients developed hypothyroidism following thyroid lobectomy within 35.7 months of follow-up. The proportion of post-lobectomy hypothyroidism was high in patients with high-normal preoperative TSH level, and the cut-off value was 2.0 mIU/L, with 67% sensitivity and 75% specificity. The quantitative titer of preoperative TG, ATA, and AMA was not significant, but the outcome of categorical analysis of two or more positivities on these three markers was significantly higher in hypothyroid patients than in euthyroid patients (28.6% vs. 3.9%, P = 0.024). The combined positivity of preoperative TSH and two or more positivities of TG, ATA, and AMA possess 100% positive predictive value and 81% negative predictive value. CONCLUSIONS The incidence of hypothyroidism following thyroid lobectomy was 21.1%. High-normal preoperative TSH and two or more positivities for TG, ATA, and AMA are good pre-operative predictive markers. Such high-risk patients need close TSH monitoring before the onset of clinical hypothyroidism.