The standard of care for the treatment of locally advanced rectal cancer is neoadjuvant chemoradiotherapy (nCRT) followed by surgery, but complete response rates are reduced. To find predictive biomarkers of response to therapy, we conducted a retrospective study evaluating blood biomarkers before nCRT. Hemoglobin (Hg), C-reactive protein (CRP), platelets, carcinoembryonic antigen, carbohydrate antigen 19.9 levels, and neutrophil/lymphocyte ratio were obtained from 171 rectal cancer patients before nCRT. Patients were classified as responders (Ryan 0–1; ycT0N0), 59.6% (n = 102), or nonresponders (Ryan 2–3), 40.3% (n = 69), in accordance with the Ryan classification. A logistic regression using prognostic pretreatment factors identified CRP ≤ 3.5 (OR = 0.05; 95%CI: 0.01–0.21) as a strong independent predictor of response to treatment. Multivariate analysis showed that CRP was an independent predictor of disease-free survival (DFS) (HR = 5.48; 95%CI: 1.54–19.48) and overall survival (HR = 6.10; 95%CI 1.27–29.33) in patients treated with nCRT. Platelets were an independent predictor of DFS (HR = 3.068; 95%CI: 1.29–7.30) and OS (HR= 4.65; 95%CI: 1.66–13.05) and Hg was revealed to be an independent predictor of DFS (HR = 0.37; 95%CI: 0.15–0.90) in rectal cancer patients treated with nCRT. The lower expression of CRP is independently associated with an improved response to nCRT, DFS, and OS.