The ret/PTC rearrangements (PTC-1, PTC-2, and PTC-3) are char- acteristic of papillary thyroid cancer (PTC). In adults, PTC-1 is com- mon and may be associated with an aggressive clinical course. The incidence and significance of ret/PTC mutations are less well under- stood in children. We examined spontaneous PTC from 33 patients (23 females and 10 males) with a median age of 18 yr (range, 6 -21 yr) and a median follow-up of 3.5 yr (range, 0 -13.4 yr). The ret/PTC mutations were identified in 15 tumors (45%), including 8 PTC-1 (8 of 15, 53%), 2 PTC-2 (2 of 15, 13%), 2 PTC-3 (2 of 15, 13%), and 3 (3 of 15, 20%) combined PTC mutations (PTC-1 and PTC-2). This distribution is significantly different (P 5 0.001, by x2 analysis) from that reported for children with radiation-induced PTC. There was no correlation between the presence or type of ret/PTC mutation and patient age, tumor size, focality, extent of disease at diagnosis, or recurrence. We conclude that ret/PTC mutations are 1) common in sporadic childhood PTC, 2) predominantly PTC-1, 3) frequently multiple, and 4) of dif- ferent distribution than that reported for children with radiation- induced PTC. (J Clin Endocrinol Metab 85: 1170 -1175, 2000)