Current treatment of rheumatoid arthritis includes systemic administration of glucocorticoids. To improve joint targeting and anti-inflammatory efficacy these glucocorticoids are encapsulated in long-circulating liposomes. The present study aimed to monitor therapeutic effects of prednisolone (PLP)-containing PEG-liposomes in murine antigen-induced arthritis (AIA) using [18F]FDG PET/CT. Mono-articular arthritis was induced in male C57Bl6/J mice. At 0, 3, 7 and 12 days after arthritis induction, inflamed joints were macroscopically scored (0 = unaffected to 4 = immobile) and [18F]FDG PET/CT images were acquired. In a second experiment, to study the feasibility to monitor therapeutic effects of PLP encapsulating PEG-liposomes, mice were treated with a single i.v. injection of PLP-containing PEG-liposomes (10 mg/kg) or empty PEG-liposomes 3 days after arthritis induction. Inflamed joints were macroscopically scored and images were acquired at − 3, 0, 4 and 9 days after treatment. PET images were analyzed quantitatively, and mice were dissected to allow histological analysis of the joints. With progression of arthritis, [18F]FDG uptake in inflamed joints increased significantly (day 0: 2.5 ± 0.9% ID/ml, day 7: 4.4 ± 0.4% ID/ml, p = 0.0159), while no changes were observed in unaffected paws (day 0: 2.5 ± 1.1% ID/ml, day 7: 2.7 ± 0.8% ID/ml, p = 0.3466). In the second experiment, macroscopic scoring revealed suppression of joint swelling after treatment with PLP-containing PEG-liposomes. In line with that, [18F]FDG uptake did not change in the treated mice (day − 3: 1.9 ± 0.3% ID/ml, day 4: 2.2 ± 0.2% ID/ml, p = 0.3466), while it increased in mice that developed arthritis (day − 3: 2.0 ± 0.2% ID/ml, day 4: 3.1 ± 0.6% ID/ml, p = 0.0225). Histological analysis confirmed therapeutic efficacy, which showed less inflammation (p = 0.0354) and bone erosion (p = 0.0298) in treated mice. These data show that [18F]FDG PET/CT could be used to monitor the progression of AIA and confirmed rapid and profound anti-inflammatory effects of PLP-containing PEG-liposomes that were also observed macroscopically and microscopically.