The prognosis and management of thyroid cancer with intermediate differentiation have been established according to reviews and small series. The aim of the present study was to determine the long-term outcome of thyroid cancer with intermediate differentiation following standardized therapy. Thirty patients (study group) with palpable tall-cell, columnar cell, diffuse sclerosing, insular and Hurthle cell variants of thyroid carcinoma,   as well as 45 follicular and 99 pure papillary controls, underwent systematic total or near-total thyroidectomy followed by at least one high dose of radioactive iodine. After a mean follow-up of 12 years, the recurrence rate was very elevated (37%) in the study group (p<0.001 versus controls), even in Stage I or Stage II subjects (p<0.001), but the disease-specific mortality in the same cohort (7%) was comparable to that of the follicular carcinoma group (p>0.28) and better than that of previous studies. Essentially, insular histology was associated with a poor outcome (recurrence 83%, mortality 33%). The recurrence was only locoregional in diffuse sclerosing carcinoma, whereas distant metastases (lung, mediastinum, bone, brain) were observed in all cases of recurrent insular, tall-cell and Hurthle cell carcinoma. In all metastatic cases, the iodophile status was permanent and no cases of dedifferentiation of metastases were described.  Despite the aggressive behavior of thyroid cancer with intermediate differentiation, early and intensive surgical and isotopic therapy may ameliorate the prognosis.