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Objective This study investigates the interaction between depression, immunity, and 5-HTTLPR among colorectal cancer (CRC) patients.Methods This prospective longitudinal study collected information on depression and lymphocyte percentages at two time points: the first cycle and the final cycles of FOLFOX chemotherapy. Clinical depression was assessed using the HADS-D score. Genotyping identified 5-HTTLPR alleles. The dependent variables were changes in the percentages of CD4+, CD8+, CD19+, and CD16/56+ lymphocytes.Results Among 104 patients, no significant direct associations were observed between changes in lymphocyte percentages and HADS-D scores. However, with the interaction of 5-HTTLPR polymorphism, the moderated regression analysis revealed two significant associations between HADS-D scores and changes in the percentages of CD4+ and CD16/56+ lymphocytes.Conclusion Changes in the percentage of CD4+ cells and CD16/56+ cells under depression were moderated by 5-HTTLPR alleles among CRC patients undergoing FOLFOX chemotherapy, suggesting a gene-environment interaction.