The aim of this study was to compare the effects of physical therapy agents (PTA) and two different intra-articular hyaluronan drugs (sodium hyaluronate (NaHA) and hylan G-F 20) on knee osteoarthritis (OA). The randomised, single-blind study, with 12 months of follow-up, was performed on 80 patients diagnosed as knee OA. The patients were randomly divided into two treatment groups: patients in group 1 were given weekly intra-articular hyaluronan treatment which consisted of either hylan G-F 20 or NaHA during the first 3 weeks and in the sixth month; PTA was applied to each patient in group 2 five times a week for 3 weeks with a series of infrared, short-wave diathermy-pulsed patterns and interferential therapy. Clinical assessments for each patient were made at 1, 3, 6, 9 and 12 months using the following measures: spontaneous pain, pain at rest, pain at night, pain on touch, pain on movement, 15 m walking time, range of motion, short form 36 (SF-36), Western Ontario and McMaster University Osteoarthritis Index (WOMAC) global assessment. There was significant improvement in all variables measured in both groups during the follow-up except the WOMAC-stiffness and range of the motion. The improvement of pain (at night, at rest, SF-36) and SF-36 social functioning subscales was greater in the PTA group. Consequently, in the subgroup analyses, there was no difference between PTA and hylan groups for this improvement. In the comparison of two drugs, the reduction of pain on touch and WOMAC-function was greater in hylan group than that of NaHA. No serious local or systemic effects were observed following injections. Although all patients had improvement, PTA was superior to hyaluronan group for no activity-related pain and functional performance. On the other hand, this study supports the preferential use of hylan over NaHA in patients with knee OA.