The 45 kDa Fas or CD95 receptor triggers apoptosis via the caspase cascade when stimulated by its ligand FasL or by agonistic Abs. Activated Fas receptors seem to oligomerize very early into SDS-stable and reducing agent-resistant microaggregates of 200-250 kDa on SDS-PAGE. However, these microaggregates have so far only been reported using agonistic anti-Fas Abs, and no results have been reported using FasL. Here, we demonstrate that the microaggregates do not form in response to FasL, while they always appear in response to the agonistic Ab, in four different cell lines and in normal lymphocytes from human blood. Therefore, the Fas microaggregates are not required for the induction of apoptosis via FasL. These results also suggest that subtle differences exist in the apoptotic pathways triggered by anti-Fas agonistic Abs and by FasL.