Early loss of proteoglycan 4 (PRG4), a lubricating glycoprotein implicated in boundary lubrication, from the cartilage surface has been associated with degeneration of cartilage and early onset of osteoarthritis. Viscosupplementation with hyaluronic acid and other macromolecules has been proposed as a treatment of osteoarthritis. However, the efficacy of viscosupplementation is variable and may be influenced by the short residence time of lubricant in the knee joint after injection. Recent studies have demonstrated the use of aldehyde (CHO) modified extracellular matrix proteins for targeted adherence to a biological tissue surface. It is hypothesized that CHO could be exploited to enhance the binding of lubricating proteoglycans to the surface of PRG4-depleted cartilage. The objective of this study was to determine the feasibility of molecular resurfacing of cartilage with CHO-modified PRG4. PRG4 was chemically functionalized with aldehyde (PRG4-CHO) and aldehyde plus Oregon Green (OG) fluorophore (PRG4-OG-CHO) to allow for differentiation of endogenous and exogenous PRG4. Cartilage disks depleted of native PRG4 were then treated with solutions of PRG4, PRG4-CHO, or PRG4-OG-CHO and then assayed for the presence of PRG4 by immunohistochemistry, ELISA, and fluorescence imaging. Repletion of cartilage surfaces was significantly enhanced with the inclusion of CHO compared with repletion with unmodified PRG4. These findings suggest a generalized approach which may be used for molecular resurfacing of tissue surfaces with PRG4 and other lubricating biomolecules, perhaps leading in the future to a convenient method for overcoming loss of lubrication during the early stages of osteoarthritis.