The Italian Registry for hairy cell leukemia (HCL) has recorded 725 patients with HCL diagnosed over 25 years. We analysed this large series of patients with the aim of providing an evaluation of changes in clinical presentation, impact of initial therapy and modifications in prognostic factors over the period of two decades. Over time, a progressive down-staging of the disease at the onset, along with a reduction of patients with severe anemia and marked splenomegaly, has been observed. A second malignancy was found in 3.7% of patients, mostly detected several years after the onset of HCL. A striking improvement of survival rates has been observed, from 58.9% survival at five years for patients diagnosed before 1985 to 87.5% at five years for patients diagnosed after 1985 (p < 0.0001). Before 1985 hemoglobin alone provided prognostic information, whereas after 1985, clinical stage and the number of leukocytes correlated better with patient outcome. Survivals at 5 and 10 years were 34.4% and 29.6% respectively for untreated patients, 58.8% and 44.1% for patients receiving chemotherapy, steroids or other drugs, 64.1% and 56.1% for splenectomized patients and 88.9% (at 5 years) for alpha interferon (IFN)-treated patients (p < 0.0001). Our findings suggest that IFN has improved the prognosis of HCL, and that it must be considered a good initial treatment for patients with HCL.