Calcium/Calmodulin-dependent kinase type II (CaMKII) is essential for various forms of synaptic plasticity. The predominant alpha- and beta CaMKII isoforms have both been shown to contribute to specific forms of plasticity at excitatory synapses, but little is known about their functions at inhibitory synapses. Here we investigated the role of both isoforms in long-term potentiation of the inhibitory molecular layer interneuron to Purkinje cell synapse (MLI-PC iLTP) upon climbing fiber (CF) stimulation. We demonstrate that deleting either the alpha- or beta CaMKII isoform affected MLI-PC iLTP. In the presence of the PP2B blocker cyclosporin A, CF stimulation elicited iLIP in Camk2b(-/-) mice, but not in Camk2b(-/-) mice. Moreover, co-activation of the MLIs and CF suppressed iLIP in wild-type mice through activation of GABA(B)-receptors, whereas it evoked iLIP in Camk2b(-/-). This reversal of the effect of alpha CaMKII activity in Camk2b(-/-) mutants upon co-activation did not critically involve protein kinase A, but depended on calcium release from internal stores. Our results indicate that alpha- and beta CaMKII isoforms in Purkinje cells can be differentially activated and serve distinct roles in controlling iLTP. We propose that the CaMKII holo-enzyme may be selectively activated by various GABA(B)-mediated pathways and that the presence of the beta CaMKII isoform determines their impact on inhibitory plasticity.