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Intra-articular corticosteroid injections are often used for short-term pain relief in patients with knee osteoarthritis (OA). This study investigates the efficacy of intra-articular corticosteroid injections in patients with symptomatic knee OA and factors that affect treatment response.This prospective, multicentered cohort study had 100 participants with radiographic evidence of knee OA enrolled. Participants received one corticosteroid injection into the affected knee and were evaluated before the injection (baseline) and at 3 weeks, 6 weeks, 3 months, and 6 months after the injection.Participants’ Visual Numeric Scale and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores improved at all time points except for the Visual Numeric Scale score at 6 months, compared with baseline scores (P < 0.001). Participants with Kellgren-Lawrence grade 1 or 2 OA saw clinical improvement in the WOMAC scores at all time points, compared with the baseline score (P < 0.01). Compared with all other subgroups, obese patients with Kellgren-Lawrence grade 3 or 4 OA had significantly worse WOMAC scores at baseline, 6 weeks, and 3 months (P < 0.01 and P < 0.01, respectively).Our findings validate previously established guidelines for nonsurgical management of knee OA and suggest that intra-articular corticosteroid injections may be an acceptable short-term management option in patients unwilling or unable to undergo surgical treatment. Obesity and OA severity affect the efficacy of intra-articular corticosteroid injections.Patients receiving intra-articular corticosteroid injections had improved pain and function. Clinicians should expect less improvement in patients with obesity and/or advanced arthritis. Clinical benefits of intra-articular injections in these patients are less predictable.