The aim of this study was to investigate the effect of parathyroidectomy (PTX) on 2-year survival and other clinical variables in hemodialysis patients with severe secondary hyperparathyroidism (sHPT), and to explore the factors influencing overall survival. A total of 363 hemodialysis patients with severe sHPT was recruited in this prospective cohort study. According to whether PTX were performed, the participants were divided into two groups: PTX group and non-PTX group. Serum sample were collected at baseline and fibroblast growth factor 23 (FGF-23) expression was measured by enzyme-linked immunosorbent assay (ELISA). All participants were followed up for 24 months. 2-year survival rate in PTX group (84.4%) was increased compared with non-PTX group (52.8%) (P < 0.001). And Kaplan-Meier curves analysis illuminated PTX group displayed a longer overall survival (P < 0.001). Change of serum FGF-23, intact parathyroid hormone (iPTH) and calcium (Ca) from Mo to M24 were greatly elevated In PTX group compared with those in non-PTX group (all P < 0.001). Besides, baseline high FGF-23 expression was associated with worse overall survival compared to low expression (P < 0.001). In addition, univariate and multivariate Cox's proportional hazards regression analysis showed that PTX was an independent protective factor for overall survival (P < 0.001), while high FGF-23 expression, high CRP, hypertension and cardiac disease were independent risk factor for overall survival (P < 0.001, P < 0.001, P = 0.010 and P = 0.005, respectively). This study indicated PTX could dramatically improve overall survival independently in hemodialysis patients with severe sHPT, and high FGF-23 expression could be served as a biomarker for poor prognosis.