Growth differentiation factor 15 (GDF-15) is a potential biomarker for colorectal cancer (CRC) and is associated with sarcopenia and cachexia. However, its clinical significance in CRC remains unclear. We investigated the clinical significance of GDF-15 in CRC patients by a unique triangular comparison of tissue and preoperative serum GDF-15 levels with host factors. We evaluated 428 tissue and 214 serum samples from 214 CRC patients. We measured tissue and serum levels of GDF-15 and assessed their association with oncological outcomes and host factors. While cancer tissue GDF-15 levels showed no significant associations with clinicopathological factors or survival, preoperative serum GDF-15 levels were significantly correlated with indicators of disease progression, such as advanced T stage and advanced pathological stage. High preoperative serum GDF-15 level was associated with poor disease-free survival and overall survival and was an independent prognostic factor for disease-free survival and overall survival. Significant correlations were observed between preoperative serum GDF-15 levels and host factors, including body mass index, psoas muscle mass index, intramuscular adipose tissue content, and C-reactive protein. In conclusion, preoperative serum GDF-15 reflects host factors such as body composition and inflammation and is a useful marker for the oncological management of CRC patients.