ObjectivesAnterior cervical decompression and fusion (ACF) has become a widely accepted surgical treatment for degenerative cervical diseases, but occasionally, significant intraoperative blood loss (SIBL), which is defined as IBL of 500 mL or more, will occur. We aimed to investigate the independent risk factors for SIBL during ACF for degenerative cervical diseases.MethodsWe enrolled 1150 patients who underwent ACF for degenerative cervical diseases at our hospital between 2013 and 2019. The patients were divided into two groups: the SIBL group (n = 38) and the non‐SIBL group (n = 1112). Demographic, surgical and radiographic data were recorded prospectively to investigate the independent risk factors for SIBL. For counting data, the chi‐square test or Fisher's exact probability test was used. Student's t‐test or the Mann–Whitney rank sum test was used for comparisons between groups of measurement data. Univariate analysis and multivariate logistic regression analysis were further used to analyze the significance of potential risk factors.ResultsThe incidence of SIBL during ACF was 3.3% (38/1150). A multivariate analysis revealed that female sex (odds ratio [OR], 6.285; 95% confidence interval [CI], 2.707–14.595; p < 0.001), corpectomy (OR, 3.872; 95% CI, 1.616–9.275; p = 0.002), duration of operation ≥150 min (OR, 8.899; 95% CI, 4.042–19.590; p < 0.001), C3 involvement (OR, 4.116; 95% CI, 1.808–9.369; p = 0.001) and ossification of posterior longitudinal ligament (OPLL) at the surgical level (OR, 6.007; 95% CI, 2.218–16.270; p < 0.001) were independent risk factors for SIBL. Patients with SIBL had more days of first‐degree/intensive nursing (p = 0.003), longer length of stay (p = 0.003) and higher hospitalization costs (p = 0.023).ConclusionFemale sex, corpectomy, duration of operation, C3 involvement and OPLL at the surgical level were independent risk factors for SIBL during ACF. SIBL in ACF was associated with more days of first‐degree/intensive nursing, longer length of stay and higher hospitalization costs.