Major histocompatibility complex class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-K^b and H2-D^b, ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-K^b and H2-D^b are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN), where protein localization correlates strongly with synaptic markers and complement protein C1q. In K^bD^b−/− mice, developmental refinement of retinogeniculate projections is impaired, similar to C1q^−/− mice. These phenotypes in K^bD^b−/− mice are strikingly similar to those in β2 m^−/−TAP1^−/− mice, which lack cell surface expression of all MHCIs, implying that H2-K^b and H2-D^b can account for observed changes in synapse plasticity. H2-K^b and H2-D^b ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.