The gastrointestinal symptoms of irritable bowel syndrome are strongly related to impaired quality of life (QOL), especially in diarrhea-predominant. The gene polymorphisms associated with serotonin, or 5-hydroxytryptamine, alter gastrointestinal symptoms and mental status. We aimed to evaluate the effects of gene polymorphisms on gastrointestinal symptoms, psychological conditions, and QOL, and compare these between patients with diarrhea-predominant irritable bowel syndrome ( n = 62) and healthy controls ( n = 64). The gene polymorphisms of 5-HTTLPR, 5-HTTVNTR, TPH1 rs453773, and TPH1 rs211105 were evaluated. Gastrointestinal symptoms, depressive state, and QOL were assessed using the Gastrointestinal Symptom Rating Scale, Self-rating Depression Scale, and Short-Form-36. Gene polymorphisms did not significantly differ in frequency between the two groups. The scores for diarrhea, abdominal pain, and indigestion significantly correlated with the physical component summary score. Only the group of patients with diarrhea-predominant irritable bowel syndrome showed a significant correlation between the TPH1 rs211105 T/T genotype and lower scores for role physical and mental health, and higher scores for indigestion and diarrhea. 5-HTTLPR l/s was associated with lower score of role emotional in the diarrhea-predominant irritable bowel syndrome and higher scores in the controls. The gene polymorphisms of 5-hydroxytryptamine signaling effected gastrointestinal symptoms and QOL, especially of the patients with diarrhea-predominant irritable bowel syndrome.