M e t h o d s Design: Randomized controlled trial (First Swiss Viscosupplementation Trial [SVISCOT-1]). Allocation: Concealed.* Blinding: Blinded (patients, outcome assessors, and data analyst).* Follow-up period: 6 months. Setting: 165 centers in Switzerland. Patients: 660 patients (mean age 63 y, 66% women) who had radiologically confirmed knee OA (Kellgren–Lawrence grade ≥ 2), with symptoms for ≥ 6 months and pain on most days in the past 3 months; an American College of Rheumatology functional class rating of II to IV; and insufficient response or intolerance to acetaminophen or nonsteroidal antiinflammatory drugs. Exclusion criteria were pregnancy, inflammatory joint disease, chondrocalcinosis, infection in or around the study knee, skin disease around the injection site, allergy or intolerance to experimental preparations, previous knee replacement, and current anticoagulant therapy or viscosupplementation in the past 6 months. Intervention: 1 cycle of 3 intraarticular injections (2 mL per treated knee) of crosslinked, high-molecular-weight hylan (Synvisc; Genzyme, Cambridge, MA, USA) (n = 222), a noncrosslinked medium-molecular-weight avian HA (Orthovisc; Anika Therapeutics, Woburn, MA, USA) (n = 219), or a noncrosslinked, low-molecular-weight bacterial HA (Ostenil; TRB Chemedica, Geneva, Switzerland) (n = 219). Injections were given at weekly intervals. Outcomes: Change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score. Secondary outcomes included WOMAC global score and stiffness and disability subscores, European Quality of Life (EuroQol) score, local adverse events (effusion or flare), need for corticosteroid injections due to local adverse events, and serious adverse events. The study had > 96% power to detect a difference between groups of 0.8 units in standardized 10-point WOMAC pain scores for comparisons of hylan with each of the 2 HAs (α = 0.025). Patient follow-up: 99% were assessed at 6 months (intention-to-treat analysis; for continuous outcomes, last outcome carried forward for 6 patients).