To explore the relationship between knee osteophytes of osteoarthritic knee and calcitonin gene-related peptide (CGRP) concentrations of serum and synovial fluid (SF). 65 patients with knee medial compartment osteoarthritis (OA) were recruited and examined with weight-bearing radiographs of the entire lower limb. The concentrations of CGRP in serum/SF were also detected in surgery. The relationship between the concentrations of CGRP in serum/SF and osteophyte scores were detected with Spearman rank correlation coefficient. CGRP concentrations in serum and SF were significantly correlated with osteophyte score of overall knee respectively (R = 0.462, P < .001; R = 0.435, P < .001). In addition, a correlation tended to be observed about the relationship between CGRP concentrations in serum and SF and osteophyte scores of medial compartment (R = 0.426, P < .001; R = 0.363, P = .003), and osteophyte scores of lateral compartment (R = 0.429, P < .001; R = 0.444, P < .001). In this study, the relationship between CGRP in serum/SF and knee osteophyte scores in different subregions were explored, which showed significant positive correlations, that possibly reflecting the contribution of CGRP influencing osteophyte formation. Positive correlations between osteophyte scores and CGRP suggest that CGRP promote the growth of osteophyte formation. It has the potential to be selected as a biomarker for the assessment of severity in knee OA patients and predict the progression of knee OA. It also provides a potential therapeutic target to delay the progression and relieve the symptom of OA.