Male urethral stricture disease (USD) is characterized by scar formation, and the molecular mechanism is still lack. In this study, we performed comprehensive proteomic landscape of USD with 12 scar tissues and 5 matched normal adjacent tissues (NATs). Comparative analysis disclosed the ECM signaling and complement cascade were overrepresented in the scar tissues, in which COL11A1, CNN2, and CD248 would play positive impacts. In addition, we revealed the diverse molecular mechanism of scar formation of USD with different ages, and proposed the potential effects of PXK in the Age 1 (< 45) patients. Furthermore, the immune infiltration of USD indicated the medicative of inhibition of complement system (C4A, C4B) in the Age 2 (≥ 45) patients. Collectively, this study provides insight into understanding the molecular mechanism of scar formation, and delivered a valuable resource for the development of therapeutic targets for USD.