Colorectal cancer (CRC) is one of the most common tumors. CRC patients are susceptible to suffering from depression. Whether the immune system of CRC patients with depression is impaired or stimulated is controversial. Possible reasons for this conflict are the involvement of confounding factors, such as the age of the patient, the stage of the CRC and the types of treatment in previous studies. To demonstrate clearly the relationship between depression and the immune system in the context of CRC, the present study included only older patients with advanced CRC who received only chemotherapy, and the study adopted immunosuppressive acidic protein (IAP) as an immune parameter for the first time. A total of 56 older patients with advanced CRC completed the Zung Self-Rating Depression Scale (SDS) and were divided into two groups according to SDS scores. The patients exhibiting depression were treated with fluoxetine until their symptoms remitted. The serum levels of IAP and the percentages of CD3-positive (CD3+), CD4+, CD8+ T lymphocytes and CD56+ natural killer (NK) cells and Neutrophil-lymphocyte ratio (NLR) were calculated at the time of enrollment and once the symptoms remitted. Correlation analyses revealed that the SDS score was positively associated with serum IAP levels but negatively associated with CD3 and CD4 levels. Among the depressed and non-depressed patients, serum IAP levels and the percentages of CD3 and CD4 cells were dramatically different. After the depression symptoms were treated, the IAP levels dramatically decreased, while the levels of CD3, CD4, CD8 and CD56 were unchanged. All of above suggested that IAP was closely correlated with depression and might be a relatively objective parameter for predicting depression.