Bacterial spot (BS) is a severe bacterial disease induced by Xanthomonas campestris pv. vesicatoria (Xcv), a pathogen that causes serious damage to pepper growth and yield. It is therefore important to study the mechanisms of pepper resistance to Xcv and to breed and promote Xcv-resistant pepper varieties. However, studies of the responses to Xcv infection in peppers at the protein level are limited. Here, we examined Xcv-induced proteomic changes in leaves of the BS susceptible bell pepper ECW and the resistant bell pepper VI037601 using the isobaric tags for relative and absolute quantitation (iTRAQ)-based protein labeling technology. A total of 6 120 distinct proteins were identified, and there were 1 289 significantly differentially accumulated proteins (DAPs) in ECW and VI037601 leaves after Xcv inoculation. Among these, 339 (250 up- and 89 down-regulated) and 479 (300 up- and 179 down-regulated) DAPs were specifically identified in ECW and VI037601, respectively, with 459 (364 up- and 95 down-regulated) similarly expressed DAPs being shared by ECW and VI037601. Based on bioinformatics analysis, many defense-associated proteins were identified as up-regulated in ECW and VI037601, especially the proteins involved in plant-pathogen interaction, phenylpropanoid biosynthesis, protein processing in the endoplasmic reticulum, and MAPK signaling pathway - plant. Moreover, we evaluated transcript levels of six differentially expressed genes from the iTRAQ results by qRT-PCR. The analysis revealed transcriptional changes that were consistent with the changes at the protein level. This study will provide a valuable resource for understanding the molecular basis of pepper resistance to Xcv infection and for improving the disease resistance of pepper cultivars.