Purpose: The infrapatellar fat pad (IPFP) is commonly resected during knee joint arthroplasty. This longitudinal study examined the associations between the maximum cross-sectional area (CSA) of the IPFP and knee cartilage volume and pain in adults without knee osteoarthritis (OA). Methods: 297 adults without baseline knee pain or a diagnosis of knee OA had MRI performed at baseline and follow-up (n = 271). IPFP maximal CSA and tibial cartilage volume were measured from MRI. Body composition was performed at baseline using bio-impedance. Knee pain was assessed at follow-up using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC). Results: A larger IPFP at baseline was associated with reduced knee pain at follow-up (OR 0.5, 95% CI: 0.3 to 0.9, p = 0.02) and lateral tibial cartilage volume loss (β: -0.9% (95% CI: -1.6, -0.1%) per annum, p = 0.03). The maximal CSA of the IPFP was predominantly located in the lateral (54.2%), rather than the medial tibiofemoral compartment (1.7%). Male gender (OR 12.0, 95% CI: 6.5 to 22.0, p < 0.001) and fat free mass (OR 1.15, 95% CI 1.04 to 1.28, p = 0.007) were both associated with a large IPFP. Conclusions: A larger IPFP predicts reduced lateral tibial cartilage volume loss and knee pain and mechanistically might function as a local shock-absorber. The lack of association between measures of adiposity and the size of the IPFP might suggest that the IPFP size is not simply a marker of systemic obesity. OA: Cartilage and Bone