Follicular lymphoma (FL) is considered an indolent but incurable disease. It remains to be clarified whether the outcome has changed after the recent introduction of novel treatment modalities. We retrospectively analyzed the outcome of 281 patients with FL treated at the Oncology Institute of Southern Switzerland from 1979 to 2007. Three diagnostic eras were considered, according to the major therapeutic changes: before 1989 ('alkylating agents era', n = 73), 1990 to 1999 ('aggressive regimens and G-CSF era', n = 119), and 2000 to 2007 ('rituximab era', n = 89). The distribution of prognostic factors was similar in the three eras. A significant improvement in cause-specific survival (CSS) was observed over time (p = 0.0088), but not in overall survival. Median CSS was 12.5 years for patients with FL diagnosed before 1989, but was not reached in the more recent groups. The estimated CSS rate at 5 years in the three eras was 80%, 86%, and 91%, respectively. The CSS of patients with FL treated at our institution has improved over the last 25 years. This improvement, already evident before the wide introduction of rituximab in clinical practice, may be a result of the sequential application of effective therapies and improved supportive care.