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The epidermal growth factor (EGF) receptor transduces the extracellular EGF signal into the cells. The distribution of these EGF receptors in the plasma membrane is heterogeneous and dynamic, which is proposed to be important for the regulation of cell signaling. The response of the cells to a physiological concentration of EGF is not homogeneous, which makes it difficult to analyze the dynamics related to the response. Here we developed a system to perform functional imaging during single particle tracking (SPT) analysis. This system made it possible to observe the cytosolic 2+ concentration to monitor the cell response while tracking individual EGF molecules and found that about half of the cells responded to the stimulation with 1.6 nM EGF. In the responding cells, the EGF receptor showed 3 modes of movement: fast (the diffusion coefficient of 0.081 ± 0.009 μm2/sec, 29 ± 9%), slow (0.020 ± 0.005 μm2/sec, 22 ± 6%), and stationary (49 ± 13%). The diffusion coefficient of the fast mode movement in the responding cells was significantly larger than that in the nonresponding cells (0.069 ± 0.009 μm2/sec, p < 0.05). The diffusion coefficient of the fast mode movement is thought to reflect the monomer-dimer equilibrium of the EGF receptor. We assumed that the feedback regulation via the 2+ signaling pathway slightly shifts the equilibrium from dimer to monomer in the responding cells. Special Issue Comment: This research paper is about the diffusion of EGF receptors in the membrane. It is therefore related with various projects in this Special Issue: the reviews about FRET41 and enzymes,42 and the projects about solving single molecules trajectories.43 [ABSTRACT FROM AUTHOR]