The formation of precise connections between retina and LGN involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the MHC Class I (MHCI) molecule H2-Db is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-Kb and H2-Db (KbDb−/−) despite intact retinal activity and basal synaptic transmission, the developmentally-regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-Db in KbDb−/− mice rescues both synapse elimination and eye specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, LTP is intact but LTD is impaired in KbDb−/− mice. This change is due to an increase in Ca 2+ permeable AMPA receptors. Restoring H2-Db to KbDb−/− neurons renders AMPA receptors Ca 2+ impermeable and rescues LTD. These observations reveal an MHCI mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-Db in functional and structural synapse pruning in CNS neurons.