Intraarticular hyaluronan injections are used to treat osteoarthritis of the knee. Acute painful swelling with a joint effusion develops locally after the injection in about 10% of cases but resolves spontaneously. Crystals are identifiable in some patients, but the mechanism in crystal-negative cases remains unknown. We report knee arthritis with inflammatory joint fluid free of organisms and crystals in two patients after Hylan GF-20 treatment for femorotibial osteoarthritis. Synovial membrane histology disclosed granulomatous synovitis with epithelioid histiocytic and multinucleate giant cells but no visible foreign bodies. These two cases suggest that crystal-negative arthritis after Hylan GF-20 injection may be ascribable to granulomatous synovitis of the foreign-body giant-cell type.