OBJECTIVE: There remains a huge unmet need for new osteoarthritis (OA) therapies. A putative reason for the failure of some therapies has been the absence of well-defined phenotypes, which might be more appropriate for specific targeted treatment. Interleukin-1 (IL-1) plays a key role in the development of OA, but the results of clinical trials targeting IL-1 in OA have to date been disappointing. METHODS: This narrative review is based on a literature search for publications describing interventions with direct Il-1 pathway inhibitors in patients with knee OA and substantiated by a description of key pre-clinical observations. RESULTS: Randomized controlled studies using IL-1 inhibition as treatment approach to knee OA have read out negatively, although trends for an improvement in pain and impact on biomarkers could be observed. However, in a post-hoc analysis of the large CANTOS trial data (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) testing an anti-IL-1 monoclonal antibody for the secondary prevention of cardiovascular events treatment arms receiving canakinumab demonstrated a substantial reduction in the incidence rate of joint replacement compared to those receiving placebo. Similar results have been reported from a post-hoc analysis of another cardiovascular risk reduction study, the low-dose colchicine 2 (LoDoCo 2) trial, raising the possibility of a beneficial effect of IL-1 inhibition in the subset of patients with metabolic phenotype. CONCLUSION: Based on the above results, it seems timely to revisit the role of IL-1 in OA, its relationship with chronic low-grade inflammation and its relevance in the subset of metabolic OA.