A novel linear multifunctional polyethylene glycol (PEG)-dexamethasone (Dex) conjugate (click PEG-Dex) was synthesized using, facile Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition (a click reaction). Des was conjugated to the click PEG via an acid-labile hydrazorie bond to allow the drug release in a pathophysiological environment. To evaluate click PEG's potential as a versatile drug delivery platform, the click PEG-Dex conjugates were tested in an adjuvant-induced arthritis (AA) rat model. In vivo optical imaging data confirmed the arthrotropism of the conjugates in the arthritic rots. A long-term treatment study revealed that a single click PEG-Dex conjugate administration provided sustained (> 15 days) amelioration of ankle joint inflammation to the AA rats. Treatment with an equivalent dose of dexmethasone phosphate sodium (free Dex) only provided temporal resolution of the arthritis, which recurred upon treatment-withdrawal. Further histological and bone mineral density comparison between the ankle joints from both click PEG-Dex and free Dux treatment groups confirmed the superior anti-inflammatory and disease modifying effects of the novel polymer -drug conjugates.