Mitogen-activated protein kinases (MAPKs) mediate plant immune responses to pathogenic bacteria. However, less is known about the cell autonomous negative regulatory mechanism controlling basal plant immunity. We report the biological role ofArabidopsis thalianaMAPK phosphatase AP2C1 as a negative regulator of plant basal resistance and defense responses toPseudomonas syringae. AP2C2, a closely related MAPK phosphatase, also negatively controls plant resistance. Loss of AP2C1 leads to enhanced pathogen-induced MAPK activities, increased callose deposition in response to pathogen-associated molecular patterns or toP. syringaepv.tomato(Pto) DC3000, and enhanced resistance to bacterial infection withPto.We also reveal the impact of AP2C1 on the global transcriptional reprogramming of transcription factors duringPtoinfection. Importantly,ap2c1plants show salicylic acid-independent transcriptional reprogramming of several defense genes and enhanced ethylene production in response toPto. This study pinpoints the specificity of MAPK regulation by the different MAPK phosphatases AP2C1 and MKP1, which control the same MAPK substrates, nevertheless leading to different downstream events. We suggest that precise and specific control of defined MAPKs by MAPK phosphatases during plant challenge with pathogenic bacteria can strongly influence plant resistance.