In the present study, we sought to generate hypotheses regarding the associations of serum levels of interleukin (IL)-17, adiponectin, and resistin with magnetic resonance imaging-measured infrapatellar fat pad (IPFP) size and signal intensity alterations in patients with knee osteoarthritis (OA). A total of 170 subjects with symptomatic knee OA (mean age 55.4 years, range 34-74, 88.2 % females) were included. IPFP volume was measured on T1-weighted spoiled gradient-recalled acquisition in the steady state images and was computed by using a software program. IPFP high signal intensity (grades 0-3) was assessed on T2-weighted fast spin echo images. Serum IL-17, adiponectin, and resistin levels were measured using an enzyme-linked immunosorbent assay. In multivariable analyses, serum IL-17 was negatively associated with IPFP volume (β = -0.185, 95 % CI -0.337 to -0.034) but positively associated with the severity of IPFP signal intensity alteration (OR 1.23, 95 % CI 1.06-1.42) after adjustment for age, sex, weight, and height. Serum adiponectin was positively associated with IPFP volume (β = 0.016, 95 % CI 0.001-0.032) but negatively associated with IPFP signal intensity alteration (OR 0.99, 95 % CI 0.98-1.00) after adjustment for covariates. Resistin was positively associated with IPFP signal intensity alteration (OR 1.13, 95 % CI 1.04-1.23) but not with IPFP volume. The significant associations of adiponectin or resistin disappeared after further adjustment for IL-17; in contrast, the significant associations of IL-17 remained after further adjustment for adiponectin. While serum IL-17 and resistin were associated with reduced IPFP volume and/or increased abnormal signal intensity alteration, serum adiponectin had opposite associations that were largely through IL-17. These findings suggest that serum adipocytokines may have a role to play in IPFP changes of knee OA.