OBJECTIVE To test the importance of the interleukin-4 (IL-4)/IL-4 receptor (IL-4R) system in osteoarthritis (OA) we evaluated soluble IL-4R (sIL-4R) levels in sera of patients with different forms of OA and healthy individuals. METHODS We recruited: 141 patients with hand OA, 70 with nodal and 71 with erosive hand OA; 64 patients undergoing total joint replacement, 34 with hip and 30 with knee OA; and 38 ethnically and geographically age-matched healthy individuals [normal controls (NC)]. RESULTS Serum sIL-4R concentration was found to be significantly higher in all OA patients than that in NC. When patients were divided into four subgroups (nodal, erosive, hip and knee OA) significant differences were present when comparing NC with each subgroup. This was true also when small-joint OA groups were compared with large-joint OA groups, the latter being associated with higher IL-4R levels. CONCLUSIONS We found increased levels of sIL-4R in OA patients compared with healthy individuals. We speculate that this reduces availability of IL-4, and its effects on chondrocytes.