: This Phase 3, randomised, double-blind, multicentre trial evaluated the efficacy and safety of a novel hyaluronic acid hydrogel cross-linked with hexamethylenediamine (HMDA-HA) compared to a conventional 1,4-butanediol diglycidyl ether cross-linked HA (BDDE-HA) in patients with mild-to-moderate knee osteoarthritis (OA). : A total of 223 adults (mean age 63.5 years; 167 women) with Kellgren-Lawrence (KL) grade I-III knee OA were randomised 1:1 to receive two intra-articular injections of HMDA-HA or BDDE-HA at baseline and at 24 weeks. The primary endpoint was changes from baseline in weight-bearing pain (WBP) on a 100 mm visual analogue scale (VAS) at Week 12, assessed in the per-protocol population. A non-inferiority margin of 10 mm was predefined. Secondary outcomes included global assessments, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index scores, responder rates, and rescue medication use [ClinicalTrials.gov: NCT06307847]. : At Week 12, least squares mean change (standard error [SE]) in WBP was -23.72 (1.88) mm in the HMDA-HA group (n = 83) and -25.99 (1.76) mm in the BDDE-HA group (n = 95), yielding a difference of 2.26 mm (95% confidence interval [CI]: -2.83 to 7.34; = 0.3825), thus demonstrating the non-inferiority of HMDA-HA to BDDE-HA. Secondary outcomes were comparable between groups. A total of 136 adverse events were reported: 44 (41.1%) in the HMDA-HA group and 32 (28.1%) in the BDDE-HA group, with no treatment-related adverse drug reactions. : A single-injection intra-articular regimen of HMDA-HA was effective and safe for the treatment of adult patients with mild-to-moderate knee OA.