An extensive analysis of the reliability of positron emission tomography (PET) after induction treatment in patients with Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL). In all, 75 untreated patients with HD (n=41) or aggressive NHL (n=34) were studied with both PET and CT scans following standard chemotherapy induction therapy (ABVD or MACOP-B) with/without radiotherapy. Histopathological analysis was performed when considered necessary. After treatment, four out of five (80%) patients who were PET(+)/CT(-) relapsed, as compared with zero out of 29 patients in the PET(-)/CT(-) subset. Among the 41 CT(+) patients, 10 out of 11 (91%) who were PET(+) relapsed, as compared with 0 out of 30 who were PET(-). The actuarial relapse-free survival (RFS) rates were 9 and 100% in the PET(+) and PET(-) subsets, respectively (P=0.00001). All five patients who were PET(+)/CT(-) underwent a lymph node biopsy: in four (80%) cases, persistent lymphoma and was confirmed at histopathological examination. Two HD patients who were PET(-)/CT(+) (with large residual masses in the mediastinum or lung) were submitted to biopsy, which in both cases revealed only fibrosis. In HD and aggressive NHL patients, PET positivity after induction treatment is highly predictive for the presence of residual disease, with significant differences being observable in terms of RFS. PET negativity at restaging strongly suggests the absence of active disease; histopathological verification is important in patients who show PET positivity.