Background: Post-operative C-reactive protein concentrations (CRP) have been reported to be associated with the development of complications following surgery for colorectal cancer (CRC). The development of complications and an exaggerated post-op CRP are associated with poor long term survival. However, whether this is due to the complication or to the CRP concentration remains unclear. Therefore, the aim of the present study was to determine whether post-op CRP concentrations, independent of post-op complications, were associated with poor long term survival following surgery for CRC. Methods: Included patients were obtained from a prospectively maintained database of CRC resections from a single institution (1999-2013). The relationship between post-op CRP concentrations and overall survival (OS) was examined using Cox regression analysis. Results: 813 patients were included. The majority of patients were > 65 yrs (67%), male (55%) and underwent elective surgery (90%). 257 patients (32%) suffered a complication. Median follow up was 49 months with 314 deaths. In those undergoing elective surgery, 508 patients had an uncomplicated post-op course. In these patients, post-op CRP was significantly lower, on post-op days 2, 3 and 4 (p < 0.001) compared to those with complications. On univariate survival analysis, CRP concentrations on day 2 (HR 1.003, p = 0.008), 3 (HR 1.003, p = 0.024) and 4 (HR 1.003, p = 0.019) were associated with poorer overall survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 2 CRP (HR 1.003, p = 0.006), age (HR 1.70, p < 0.001) and TNM stage (HR 1.61, p < 0.001) were independently associated with poorer survival. On multivariate analysis, adjusting for age, sex and TNM stage, day 3 CRP (HR 1.003, p = 0.030), age (HR 1.70, p < 0.001) and TNM stage (HR 1.63, p < 0.001) were independently associated with poorer survival. Conclusions: In patients undergoing elective surgery for CRC who have an uncomplicated post-op course, the post-op day 2 and 3 CRP concentrations were independently associated with poorer survival. Therefore, CRP could be considered a potential therapeutic target in future attempts to try and improve outcomes following surgery for CRC.