BackgroundOsteoarthritis (OA) is a leading cause of pain and disability and has a negative impact on patients’ quality of life. Platelet-rich plasma (PRP) has emerged as a promising treatment for various orthopaedic conditions, such as tendinopathies, nonunion, and arthritis of the knee. We sought to determine whether a single intra-articular platelet-rich plasma injection has better functional and pain outcomes when compared with multiple (two) articular platelet-rich plasma injections given in the early stages of OA of the knee, measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) and the visual analogue scale for pain (VAS) at the sixth week, third month, and sixth month.Materials and methodsThe prospective observational study was conducted among patients diagnosed with early OA who presented to the Department of Orthopaedics, R. L. Jalappa Hospital and Research Centre, Kolar, Karnataka, India, between January 2020 and June 2021. A total of 64 patients were divided into: (i) S-PRP group (34 patients), which received a single PRP injection, and (ii) M-PRP group (30 patients), which received multiple (two) PRP injections, one on presentation and the second in the thirdmonth. VAS and WOMAC scores to assess functional outcomes were used at the first visit before the intervention and at the sixth week, third month, and sixth month.ResultsThe average age of the patients was 55.26 years in the S-PRP group and 51.13 years in the M-PRP group. Both genders were equal among study participants in the M-PRP group, but 79.4% were females in the S-PRP group. In the S-PRP group, 74% had grade II OA and 26% had grade I OA. In the M-PRP group, 60% had grade II OA and the remaining 40% had grade I OA. The decreasing trend of pain and functional limitation, which was measured by VAS and WOMAC, respectively, was observed in both groups at pre-injection, sixth week, third month, and sixth month. These differences were statistically significant. The mean difference in VAS score between the pre-injection period and at six months was 4 in the S-PRP group, whereas it was 5.77 in the M-PRP group, and this was statistically significant (p-value = 0.001). Thus, multiple PRP injections have a greater response to pain reduction when compared to single PRP injections, according to the VAS score. According to the WOMAC score, there is no statistically significant difference in the treatment response with PRP injection between the S-PRP and M-PRP groups at any follow-up period.ConclusionAccording to the VAS score, single PRP injections have a lower pain score than multiple PRP injections until three months of follow-up, while at six months, single PRP injections have no better effect than multiple PRP injections. But multiple PRP injections have a higher reduction in the intensity of pain when compared to single PRP injections during the follow-up period. According to the WOMAC score, there is no statistically significant difference in the treatment response with PRP injection between S-PRP and M-PRP groups.