Minimal residual disease (MRD) was evaluated in 30 patients with follicular or mantle cell non-Hodgkin's lymphoma (NHL) undergoing an intensive treatment with high-dose sequential (HDS) chemotherapy and peripheral blood progenitor cell (PBPC) autografting. To minimize the potential tumor cell contamination, PBPC harvests were scheduled at the end of HDS pretransplant phase. All patients had advanced-stage disease and most of them presented with bone marrow (BM) involvement. A tumor marker could be generated in 90% of patients using bcl-2 or lg heavy-chain genes. MRD was analyzed on PBPC, BM harvests, and after autografting by polymerase chain reaction (PCR). All evaluable follicular and 6 of 9 mantle cell patients achieved clinical complete remission. PCR negativity of PBPC and/or BM harvests was documented in 68% of follicular and 12% of mantle cell lymphomas. Molecular remission of PBPC and/or BM harvests was achieved in 9 of 15 patients with overt marrow involvement and in all patients with only molecular marrow infiltration at onset. Molecular follow-up was conducted on 14 patients: all 7 evaluable patients who received at least one PCR-negative graft maintained the negative status at a median follow-up of 24 months and none of them relapsed so far. Thus, the results show that (1) a molecular marker to monitor MRD can be obtained in most follicular and mantle cell NHL patients, (2) the HDS regimen may provide PCR-negative PBPC and/or BM harvests even from patients with BM disease, and (3) autograft with at least one PCR-negative harvest is associated with a durable clinical and molecular remission.