Previous ultrastructural and cytochemical examination of the HCMV inoculum as used in the laboratory enabled the distinction of 7 morphologically different types of structures including complete virions, other enveloped and non-enveloped particles and dense bodies (Topilko and Michelson, 1994). In the present study, electron microscopy was used to investigate the kinetics and modalities of the earliest interactions between these components of inoculum and human foreskin fibroblasts (FSF). Particles did not attach to cells during incubation at 4 degrees C. However, when FSF were adsorbed with virus for 30 seconds at 37 degrees C, HCMV particles attached to the cell surface. Particle attachment was mediated by fine virus envelope-cell membrane bridges. Within 60 seconds, numerous virions had fused with cell membranes, and nucleocapsids had entered the cytoplasm. Enveloped particles with translucent cores, designated non-infectious enveloped particles (NIEP), were also seen to enter cells in the same way and with the same kinetics as complete virions. Uptake of dense bodies followed the same kinetics and mode of penetration as complete virus particles. These findings reveal that in vitro, enveloped particles (virions and NIEP) and dense bodies enter the cytoplasm of the host cell simultaneously, immediately (< 60 seconds) after contact with the cell membrane. Our results suggest that activation of immediate early cellular responses may not simply be due to transmembrane signal transduction, but that hyperimmediate entry of these elements into cells may participate directly in host cell activation.