Background Platelet-rich plasma (PRP) and hyaluronic acid (HA) intra-articular knee injections are widely accepted as modalities to treat pain and functional limitation associated with knee osteoarthritis. So it can be assumed that a combination of both HA and PRP in one injection could supply many advantages for cartilage repair. It adds the benefit of HA viscosupplementation with PRP regenerative properties. This study aims at finding out whether blending HA with PRP gives better clinical and functional results when compared with PRP intra-articular injection alone. Patients and methods A prospective, double-blind, randomized, multicenter clinical trial was conducted. It included 58 patients with average age of 35 years (range: 29–49 years), started on January 2016 and ended on June 2017. Each patient had initial assessment, and then were followed up after 6 months and then at 12 months. They were randomized into two groups: group 1 (PRP) (24 cases) was injected with PRP only and group 2 (PRP+HA) (34 cases) was injected with PRP plus highly cross-linked sodium hyaluronate. Results Initially, both groups were matched in age and BMI, with P value more than 0.05. Both groups were also matched on their initial assessment by the three clinical assessment methods, namely, knee society score, global impression of changes, and the Western Ontario and McMaster Universities Arthritis Index, with P value more than 0.05. Comparing groups 1 and 2 regarding the follow-up results showed, globally, no significant superiority of group 2 (PRP+HA) over group 1 (PRP). It was quite apparent in global impression of changes at 6 and 12 months, and in Western Ontario and McMaster Universities Arthritis Index at 6 and 12 months, with P value more than 0.05. Knee society score gives results with group 1 (PRP group) at 6 month and after 1 year follow-up, which were better than the results of group 2 (PRP+HA), with P value less than 0.05. Follow-up of each group of patient separately at 6 months and 1 year showed that each of them has highly significant improvement regarding pain and functional outcome, with P value less than 0.001. Conclusion PRP intra-articular injection appears to improve pain and function in middle-aged women with mild to moderate knee osteoarthritis, with no added benefit of blending HA with PRP during injection.