Background: Hemodialysis (HD) patients occasionally experience minor asymptomatic elevation in C-reactive protein (CRP) levels, which may be associated with difficulty in managing renal anemia using erythropoiesis-stimulating agents (ESAs). Here, we assessed whether elevation of CRP predicts future incidences of ESA hyporesponsiveness. Methods: A total of 2,956 HD patients lacking ESA hyporesponsiveness and infectious diseases were enrolled, and the association between CRP levels and incidence of ESA hyporesponsiveness was assessed. CRP levels were divided into 4 categories (normal [<1.0 mg/l], mild [1.0≤ CRP <3.0 mg/l], moderate [3.0≤ CRP <10.0 mg/l] and high [≥10.0 mg/l]). The primary outcome was the cumulative incidence of ESA hyporesponsiveness, defined as a failure to achieve hemoglobin level ≥10 g/dl despite receiving high doses of ESAs (≥9,000 U/week recombinant human epoetin [rHuEPO]-α or rHuEPO-β and ≥60 μg/week darbepoetin-α) during 12 months of follow-up. Results: The cumulative incidence of ESA hyporesponsiveness was 134 (4.8%) occurrences over 4 months and 300 (12.4%) over 12 months. The elevated CRP groups had significantly higher incidence of ESA hyporesponsiveness over 4 months of follow-up than the normal reference group (adjusted relative risk [RR] 1.6, 95% CI 1.0-2.6 for moderate; adjusted RR 2.5, 95% CI 1.5-4.1 for high). Furthermore, the association remained consistent even over 12 months (adjusted RR 1.4, 95% CI 1.0-1.8 for moderate; adjusted RR 1.6, 95% CI 1.1-2.4 for high). Conclusions: Elevated CRP levels were associated with future incidence of ESA hyporesponsiveness from low-grade inflammation (3.0≤ CRP <10.0 mg/l).