AbstractFrailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan® assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid‐binding proteins, including fatty acid‐binding protein (FABP) (p = 1.96 × 10−19) and FABPA (p = 8.10 × 10−16), leptin (p = 1.43 × 10−14), and ANTR2 (p = 7.95 × 10−20). Pathway analysis with the top 143 frailty‐associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell‐to‐cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10−16). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10−16) than observed frailty (r = 0.37, p = 1.2 × 10−15). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.