The retina adapts to the temporal contrast of the light inputs. One component of contrast adaptation is intrinsic to retinal ganglion cells: temporal contrast affects the variance of the synaptic inputs to ganglion cells, which alters the gain of spike generation. Here we show that slow Na+ inactivation is sufficient to produce the observed variance adaptation. Slow inactivation caused the Na+ current available for spike generation to depend on the past history of activity, both action potentials and subthreshold voltage variations. Recovery from slow inactivation required several hundred milliseconds. Increased current variance caused the threshold for spike generation to increase, presumably because of the decrease in available Na+ current. Simulations indicated that slow Na+ inactivation could account for the observed decrease in excitability. This suggests a simple picture of how ganglion cells contribute to contrast adaptation: (1) increasing contrast causes an increase in input current variance that raises the spike rate, and (2) the increased spike rate reduces the available Na+ current through slow inactivation, which feeds back to reduce excitability. Cells throughout the nervous system face similar problems of accommodating a large range of input signals; furthermore, the Na+ currents of many cells exhibit slow inactivation. Thus, adaptation mediated by feedback modulation of the Na+ current through slow inactivation could serve as a general mechanism to control excitability in spiking neurons.