BACKGROUND: There is no cure for knee osteoarthritis (KOA) and typically patients live approximately 30-years with the disease. Most common medical treatments result in short-term palliation of symptoms with little consideration of long-term risk. This systematic review aims to appraise the current evidence for the long-term (≥12 months) safety of common treatments for knee osteoarthritis (KOA). METHODS: Cochrane Database of Systematic Reviews, Medline and PubMed were systematically searched from 1990 to July 2017, inclusive. Inclusion criteria were 1) peer-reviewed publications investigating treatments for KOA referred to in the Australian Clinical Care Standard and/or Therapeutic Guidelines: Rheumatology 2) specifically addressing safety of the treatments 3) with ≥12 months of follow-up and 4) Downs and Black quality score ≥ 13. RESULTS: Thirty-four studies fulfilled the inclusion criteria. Lifestyle modifications (moderate exercise and weight loss), paracetamol, glucosamine, Intraarticular Hyaluronic Acid (IAHA) and platelet-rich-plasma (PRP) injections have a low risk of harm and beneficial ≥12 month outcomes. Although Nonsteroidal Anti-inflammatory Drugs (NSAIDs) provide pain relief, they are associated with increased risk of medical complications. Cortisone injections are associated with radiological cartilage degeneration at > 12 months. Arthroscopy for degenerative meniscal tears in KOA leads to a 3-fold increase in total knee arthroplasty (TKA). TKA improves primary outcomes of KOA but has a low rate of significant medical complications. CONCLUSIONS: Given the safety and effectiveness of lifestyle interventions such as weight loss and exercise, these should be advocated in all patients due to the low risk of harm. The use of NSAIDs should be minimized to avoid gastrointestinal complications. Treatment with opioids has a lack of evidence for use and a high risk of long-term harm. The use of IAHA and PRP may provide additional symptomatic benefit without the risk of harm. TKA is associated with significant medical complications but is justified by the efficacy of joint replacement in late-stage disease. TRIAL REGISTRATION: PROSPERO International prospective register for systematic reviews; registration number CRD42017072809 .