OBJECTIVES: The present study investigated the cost-effectiveness of a novel, intra-articular, extended-release formulation of triamcinolone acetonide (TA-ER) in comparison to other methods for treating knee osteoarthritis (OA) pain. METHODS: Clinical outcome data from 324 patients enrolled in three Phase 2 and Phase 3 randomized trials (NCT01487161, NCT02116972, NCT02357459) evaluating an investigational intra-articular corticosteroid formulation (FX006 40 mg) for treatment of knee OA pain were used. In these studies, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC-A [Pain], -B [Stiffness], -C [Physical Function]) data were assessed at baseline and at 4-week intervals through 12 (one study) or 24 weeks (2 studies) post-treatment. Health Utilities Index Mark 3 (HUI3) scores were calculated from WOMAC values. Cost-effectiveness was assessed using cost per quality-adjusted life years ($/QALY) and the incremental cost-effectiveness ratio (ICER) versus other knee OA treatments, including conventional care with non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, physical therapy, and assistive devices (CC); prescription NSAIDs (diclofenac); and hyaluronic acid treatment regimens with 1-5 intra-articular injections (HAs); based upon 2016 WAC pricing. RESULTS: TA-ER demonstrated sustained significant improvements from baseline in all WOMAC components through 24 weeks, with concordant improvements in HUI3; peak HUI3 gain from baseline was 0.229 at week 4. Overall, TA-ER treatment produced an average QALY gain from baseline of 0.189 per 6 months, higher than published for CC (0.030), diclofenac (0.078) and HAs (average 0.110). At a hypothetical drug cost of $500, TA-ER yields a $/QALY estimate of $3,201, in comparison to other treatments: diclofenac ($2,708), CC ($10,717), and HAs (average $13,267). TA-ER at this treatment cost provided ICERs of $1,783 versus CC, $3,549 versus diclofenac, and was the dominant strategy versus HA injection regimens. CONCLUSIONS: Intra-articular TA-ER injection provides sustained positive clinical outcomes, and if priced similarly to HA therapies, will be a cost-effective therapy for treating knee OA pain.