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Introduction It is increasingly recognised that host-related factors may be important in determining cancer outcome. The aim of the present study was to examine the relationship between patient physiology, the systemic inflammatory response and survival after resection of colorectal cancer. Methods Patients undergoing potentially curative resection of colorectal cancer were identified from a prospectively maintained database. Data was collected on patient demographics, comorbidity, lifestyle, tumour pathology and operative procedure. The modified Glasgow Prognostic Score (mGPS) was used to assess inflammatory response. Physiology was assessed according to Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) criteria. To assess the individual contribution of each physiological variable a mean score per patient was calculated. Multivariate 5 year survival analysis with calculation of hazard ratios (HR) was carried out. Results 320 patients who underwent resectional surgery for colorectal cancer between 1997 and 2006 were included. The median follow up was 74 months. During this period there were 136 deaths; 83 cancer related and 53 from other disease. On multivariate analysis, Dukes stage (HR 2.47, p<0.01), mGPS (HR 1.67, p<0.01), physiology score (HR 1.38, p<0.05) and emergency surgery (HR 2.32, p<0.05) were independent predictors of cancer specific survival. Overall survival was predicted by Dukes stage (HR 1.69, p<0.01), mGPS (HR 1.55, p<0.01), physiology score (HR 1.38, p<0.05) and smoking (HR 1.55, p<0.05). POSSUM physiology score and mGPS were directly associated (p<0.01). Individual components contributing most to physiology score were poor cardiac function, low haemoglobin and ECG abnormality. Those related to mGPS were poor cardiac function, low haemoglobin and age. Conclusion POSSUM physiology scores and elevated systemic inflammatory response can independently predict cancer specific and overall survival in colorectal cancer. These results highlight the importance of host-related factors in determining outcome. The results also suggest that compromised cardiac function is an important factor underpinning these relationships.