We have investigated the characteristics and mechanism of activity- dependent decreases in synaptic effectiveness in visual cortex. Repetitive, low-frequency stimulation (LFS) of either layer IV or the white matter of visual cortical slices was shown to result in a long- term depression (LTD) of intra- and extracellularly recorded synaptic responses in layer III. In preparations in which responses to stimulation of two independent pathways could be monitored, LFS of one pathway produced LTD of responses to test stimulation of that input only, showing that this form of LTD is homosynaptic. This form of LTD was dependent on the frequency and/or pattern of conditioning stimulation and on activation of NMDA receptors. Okadaic acid, an inhibitor of protein phosphatases 1 and 2a, inhibited LTD, but had no effect on induction of long-term potentiation. In all of these respects, LFS-induced LTD in visual cortex closely resembles what has been recently documented in hippocampus. The combined data support a model in which LTD is triggered by a modest elevation in postsynaptic Ca2+ and activation of protein-serine, threonine phosphatases.