This study was conducted to determine if nasal salmon calcitonin has additional beneficial effects on clinical symptoms, serum NO, IL-1 beta, matrix metalloproteinase 3, urinary C-terminal telopeptide type II collagen (CTX-II) levels and MRI findings in knee osteoarthritis (OA) when used concomitantly with exercise therapy. Fifty female patients with knee OA were randomized into two groups. The first group (n = 30) received 200 IU/day nasal salmon calcitonin and a home exercise program; the second group (n = 20) received a home exercise program for 6 months. Compared with baseline, while significant improvements were observed in visual analogue scale (VAS), WOMAC pain, physical function scores, 20-m walking time (P<0.001) and WOMAC stiffness score (P=0.041) in the first group, walking and resting VAS, and WOMAC physical function scores were improved (P=0.029) in the second group after treatment. Significantly increased levels of serum NO and urinary CTX-II (P<0.001) and significant improvements in the area of medial femoral condyle (P<0.05) were noted only in the first group. There were significant differences in VAS activation values (P=0.032) and NO levels (P<0.001) in the favor of the first group. In conclusion, nasal salmon calcitonin may have possible chondroprotective effects besides its known effects on symptoms in patients with knee OA.