PURPOSE: Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification. METHODS: A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification). RESULTS: Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both. CONCLUSIONS: In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.