Two hundred fifty-nine previously untreated patients with low-grade non-Hodgkin's lymphomas (NHLs), Ann Arbor stages III and IV, entered a randomized multicenter trial comparing the therapeutic effect of chlorambucil/prednisone (ChP) vs. CHOP. All patients had symptomatic disease. The therapeutic aim was to achieve an asymptomatic state in the ChP group (n = 132), while in CHOP-treated patients (n = 127) the intention was to reach a complete remission (CR). The response rate (CR+PR at 8 months) was 36% in the ChP and 60% in the CHOP group (p < 0.01). Three and 5-year survival rates were 59% and 41% in the ChP group and 64% and 44% in the CHOP group. The corresponding median survival times were 46 and 52 months. After correction for intercurrent deaths, the overall 5-year survival was 49% for ChP and 54% for CHOP-treated patients. The differences were statistically not significant. The time from diagnosis to randomization (time with asymptomatic disease) was longer than one year in half of the patients. The median survival time from diagnosis was 68 months, with no differences between the treatment groups. In all histological subgroups (CLL, IC, CC, and CB-CC), a higher remission rate was seen with the CHOP regimen but with no statistically significant influence on survival. Comparing patients below and above 65 years of age, no significant difference in survival was noted between the two treatment groups. The results do not support the use of intensive chemotherapy as first-line therapy in symptomatic low-grade NHL.