We evaluated the association between weight change in middle-aged adults and papillary thyroid cancer (PTC) based on a largescale case-control study. Our study included data from 1551 PTC patients (19.3% men and 80.7% women) who underwent thyroidectomy at the 3 general hospitals in Korea and 15,510 individually matched control subjects. The subjects' weight history, epidemiologic information, and tumor characteristics confirmed after thyroidectomy were analyzed. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were determined for the annual average changes in weight and obesity indicators (body mass index (BMI), body surface area, and body fat percentage (BF%) in subjects since the age of 35 years. Subjects with a total weight gain-10 kg after age 35 years were more likely to havePTC(men,OR, 5.39, 95%CI, 3.88-7.49; women,OR, 3.36, 95% CI, 2.87-3.93) compared with subjects with a stable weight (loss or gain<5 kg).Amarked increase inBMI since age 35 years (annual average change of BMI -0.3 kg/m2/yr) was related to an elevated PTC risk, and the association was more pronounced for large-sized PTC risks (<1cm, OR, 2.34, 95% CI, 1.92-2.85; -1 cm, OR, 4.00, 95% CI, 2.91-5.49, P heterogeneity=0.005) compared with low PTC risks. Weight gain and annual increases in obesity indicators in middleaged adults may increase the risk of developing PTC.