ETHNOPHARMACOLOGICAL RELEVANCE: Chinese patent medicine Tenghuang Jiangu tablet (THJGT) is frequently used to treat knee osteoarthritis (KOA). AIM: This prospective multicenter registry study investigated the effectiveness and safety of THJGT in treating KOA. MATERIALS AND METHODS: Patients with KOA aged 50-75 years were preferentially treated with THJGT, other nonsurgical conventional treatments (CTs), or both. The treatment duration was 8 weeks, with follow-ups at weeks 4 and 8. The visual analog scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were the efficacy assessments. Adverse events and drug reactions were evaluated to assess the safety of THJGT. Propensity score matching (PSM) was used for the subgroup analysis. RESULTS: From September 2019 to January 2021, a total of 2995 participants were included, with 1471 in THJGT group, 490 in CT group and 1034 in THJGT + CT group. After treatment, the VAS and WOMAC scores in the three groups improved significantly (P <
0.001). At week 8, the VAS scores in the THJGT group significantly improved, were lower than those in the CT group (P <
0.01), and were comparable to those in the THJGT + CT group (P = 0.623). The WOMAC scores significantly improved (P <
0.001), with no differences between groups (P >
0.05). The WOMAC pain and stiffness scores were better in the THJGT + CT than in the THJGT and CT groups. PSM revealed that the WOMAC pain and stiffness scores were significantly lower in the THJGT than in the nonsteroidal anti-inflammatory drugs (NSAID) group (P <
0.01 and 0.001). Adverse events were higher in the CT and THJGT + CT groups (P <
0.001). CONCLUSION: THJGT is effective and safe for treating KOA, particularly in improving stiffness symptoms.