We used an ultrastructural approach to analyze morphologic changes in isolated human lung mast cells during IgE-induced degranulation. We found that after stimulation with anti-IgE, mast cell cytoplasmic granules became swollen, their complex matrix patterns became altered, and their membranes fused to produce chains of granules which enlarged to become tortuous cytoplasmic degranulation channels. These channels eventually opened to the surface of the cell at multiple points in the circumference of the cell. Loss of altered granule matrix occurred in the absence of extrusion of formed granules or granular structures to the exterior of the cell. As channels opened to the exterior a remarkable activation of cell surface occurred. This was initially characterized by elongation and increasing complexity of surface processes. At later times, many free membranes were found adjacent to small mast cells which had diminished granule numbers and smooth surfaces. All of these changes were seen in morphologically undamaged cells and constitute a readily recognizable sequence of IgE-induced release events in isolated human lung mast cells.