From the Southwestern Ontario database, one of the largest primary-care datasets in Canada, 1,263 patients with osteoarthritis (OA) of one or both knees were identified who received two consecutive series of intra-articular (IA) injections of hylan G-F 20 preparation and no other prescribed OA medications, and were evaluated fully between 2006 and 2012. A cohort of 3,318 demographically matched OA patients who had not been treated with IA injection therapy was identified from the same database for comparison. Responses to therapy were assessed by means of a 10-point visual analog scale (VAS) for pain at rest and after completion of a 6-minute walk test (6MWT), while physical capacity was measured by performance in the 6MWT itself. After two cycles of hylan G-F 20 therapy, the average VAS score for pain at rest declined from 7.82±1.27 at baseline to 4.16±1.51 (average change 3.66±1.78, significantly more than the reduction of 3.12±2.03 seen in the reference group [ P<0.012]) and the average VAS score for pain after the 6MWT decreased by 5.56±1.74 points (from 9.58±0.4 at baseline to 4.02±1.67 at the final assessment), a significantly larger change than that seen in the reference group (Δ2.99±1.85; P<0.001 for intergroup comparison). Distance walked in the 6MWT increased on average by 115 m, significantly more than that seen in the reference group (Δ91 m; P<0.001 for intergroup comparison). These findings from a primary-care database suggest sustained benefits in terms of pain and physical function from repeat cycles of IA injections of hylan G-F 20 and no other prescribed OA medications in adults with OA of the knee.