Many fungal and oomycete pathogens differentiate a feeding structure named the haustorium to extract nutrition from the plant epidermal cell. The atypical resistance (R) protein RPW8.2 activates salicylic acid (SA)-dependent, haustorium-targeted defenses against Golovinomyces spp., the causal agents of powdery mildew diseases on multiple plant species. How RPW8.2 activates defense remains uncharacterized. Here, we report that RPW8.2 interacts with the phytochrome-associated protein phosphatase type 2C (PAPP2C) in yeast and in planta as evidenced by co-immunoprecipitation and bimolecular fluorescence complementation assays. Down-regulation of PAPP2C by RNA interference (RNAi) in Col-0 plants lacking RPW8.2 leads to leaf spontaneous cell death and enhanced disease resistance to powdery mildew via the SA-dependent signaling pathway. Moreover, down-regulation of PAPP2C by RNAi in the RPW8.2 background results in strong HR-like cell death, which correlates with elevated RPW8.2 expression. We further demonstrate that hemagglutinin (HA)-tagged PAPP2C prepared from tobacco leaf cells transiently transformed with HA-PAPP2C possesses phosphatase activity. In addition, silencing a rice gene (Os04g0452000) homologous to PAPP2C also results in spontaneous cell death in rice. Combined, our results suggest that RPW8.2 is functionally connected with PAPP2C and that PAPP2C negatively regulates SA-dependent basal defense against powdery mildew in Arabidopsis.