Chick embryonic sensory ganglia cells have two specific nerve growth factor receptors, site I and site II receptors, whose binding affinities differ by two orders of magnitude. As judged by both steady state binding and kinetic data, the two receptors behave independently. The rate of dissociation of the labeled nerve growth factor from site I receptors is increased in the presence of unlabeled nerve growth factor even when its concentration is below that of the labeled growth factor used to equilibrate the cells, a phenomenon which cannot be explained by negative cooperativity. Site I receptors are present only on neurons while site II receptors are present on both neurons and nonneuronal cells. At the concentration of nerve growth factor which produces half maximal stimulation of neurite outgrowth 8% of site I and 0.1% of site II receptors are occupied. This occupancy of site II receptors falls to about 0.01% with bisdesarginine beta nerve growth factor, a derivative which is as biologically active as the unmodified factor but which binds with lower affinity to site II receptors. These data support the idea that interaction of nerve growth factor with site I receptors is responsible for the initiation of neurite outgrowth.