BackgroundLack of confidence in hyaluronic acid injections (IAHA) for osteoarthritis (OA) may result from conflicting guidelines and pooling of results for different molecular weight products. ObjectivesThe objectives were to determine responder rates to injections of very high molecular weight (VHMW-HA) vs high molecular weight (HMW-HA) injections for knee OA and treatment efficacy measured by the interval between follow-up injections. MethodsA retrospective analysis of a 15-year cohort from a single centre. Inclusion criteria: adults with KL Grade III or IV knee OA treated with hyaluronic acid injections. Subjects were stratified into two groups based on the molecular weight of the hyaluronic acid. Outcome measures were responder rates with improvement in WOMAC scores of >30% from baseline versus non-responders; those with a response lasting >6 months after each injection were considered sustained responders. Results2037 (female 1467 (72.02%), and male 570 (27.98%)) patients were treated. The overall primary responder rate was 73.44% (1496). VHMW-HA had significantly higher primary responders (75.21% vs. 70.22%, p=0.015) and significantly lower non-responders (24.79% vs. 29.78%, p=0.015). As a subset of primary responders, the sustained responders had greater responses with VHMW-HA vs. HMW-HA (85.54% vs.67.06% p<0.0001) and lower dropouts (14.46% vs 32.94% p<0.0001). The average interval between the first and the third injections was longer for VHMW-HA vs. HMW-HA - 5.67 years vs 1.95 years. (p<0.0001) Conclusion73.44% of subjects responded to treatment with IAHA. The sustained response was greater in VHMW-HA vs HMW-HA and VHMW-HA has a longer duration of effect than HMW-HA.