We investigated whether the diffuse sclerosing variant of papillary carcinoma (diffuse sclerosing PC) and insular carcinoma (IC), two different subforms of differentiated carcinoma of the thyroid gland, have different clinical behaviors and prognosis in order to select appropriate therapy. The characteristics of clinical presentation, and outcome after therapy were evaluated in a series of 113 patients (18 males and 95 females) with differentiated thyroid carcinoma treated with the same protocol, of which 7 had diffuse sclerosing PC and 6 had IC; within this series, patients with diffuse sclerosing PC and IC were compared with 76 cases of papillary carcinoma (PC) and 24 cases of follicular carcinoma (FC), respectively. Diffuse sclerosing PC patients were younger (23 ± 9 vs. 38 ± 16 years) and had a higher degree of lymphatic metastases at diagnosis (100%) than patients with PC (47%). Five of 7 patients with diffuse sclerosing PC were alive and without evidence of disease compared to 34 of 76 patients with PC at follow- up (6.4 ± 5.1 and 7.9 ± 7 years, respectively). No prognostic differences were found between them. IC showed a more advanced stage of disease at diagnosis and a more aggressive clinical course with a higher percent of metastases and mortality than patients with FC at follow-up (1 patient died and 5 were alive with persistent disease at 4.8 ± 3.7 years for IC; 22 were alive, 13 of them with persistent disease; and 2 died at 8.4 ± 5.3 years for FC). We conclude that patients with diffuse sclerosing PC do not require a different treatment than that given to PC patients, while in contrast, IC cases need a more aggressive therapeutic approach.