Vascular smooth muscle cells (VSMCs) are key players in vascular dysfunction associated with hypertension, where phenotypic switch is a fundamental process. While various transcription factors have been implicated in this process, the proteomic signature associated with phenotypic switching in human hypertension is unknown. Using high fidelity proteomic analysis, we characterized the proteome profile of VSMC in human hypertension. VSMC derived from resistance arteries from normotensive (NT) and hypertensive (HT) subjects were studied. Protein expression and cell migration were assessed by immunoblotting and wound healing assay. VSMC proteins were labelled with isobaric tandem mass tags and identified by liquid chromatography tandem mass spectrometry. The oxidative proteome was assessed using stable isotope-labelled iodoacetamide to target free reduced cysteine thiols. VSMCs from HT subjects exhibit reduced expression of α-SMA (0.05±0.01 vs NT:0.20±0.03, p<0.05), increased expression of the proliferation marker, PCNA (0.162±0.3 vs NT:0.51±0.004, p<0.05), and increased migration (54.68±2.86 vs NT:23.37±8.36, p<0.05). The proteomic analysis identified 207 proteins upregulated in HT subjects (fold change>1.5, p<0.05). There were no changes in protein expression of pathways related to the contractile phenotype (MYH11, CNN1, TAGLN, TPM, CALD1). However, extracellular matrix (ECM) proteins such as COL1A1, COL9A1, COL10A1, FBN1, FBLN1 were increased in cells from HT (fold change>1.5, p<0.05), suggesting a switch to a fibroblast-like phenotype in hypertension. Expression of proteins related to the interferon and IL-1β pathways (IFIT1, IFIT2, IFIT3, MX1, MX2, ABCA1, ABCA2, IL1RAP, CD36, ICAM1) were also increased in cells from HT subjects (fold change>1.5, p<0.05). Considering the importance of oxidative stress in hypertension, we assessed the VSMC oxidative proteome. Results demonstrate that ECM proteins, such as COL11A1 and COL16A1, were highly oxidized in cells from HT (fold change>1.5, p<0.05). Our study provides new insights into the proteomic changes that define the vascular phenotype in hypertension and highlights candidate targets that may drive phenotypic switching associated with vascular injury in hypertension.