Abstract: Objective To investigate the value of serum 5-hydroxytryptamine （5-HT） and interleukin-6 （IL-6） levels in predicting depression in patients with Alzheimer’s disease （AD）. Methods Ninety-six AD patients without depression were prospectively recruited and followed-up for 2 years. During follow-up, all patients were divided into the AD complicated with depression group （depression group） and AD without depression group （non-depression group） according to whether they were complicated by depression. Baseline data and serum 5-HT, IL-6, brain-derived neurotrophic factor （BDNF） and glucocorticoid （GC） levels at baseline were compared between two groups. The correlation between serum 5-HT and IL-6 levels and HAMD score was assessed by Pearson correlation analysis. The effect of serum 5-HT and IL-6 levels on depression in AD patients was evaluated by logistic regression analysis, and the receiver operating characteristic （ROC） curve was drawn. Results A total of 87 patients were included after 9 patients were excluded. The baseline data were comparable between two groups （all P > 0.05）. In the depression group（n = 37）, serum 5-HT level was significantly lower, whereas serum IL-6 level was significantly higher compared with those in the non-depression group （n = 50）（both P < 0.01）. Serum 5-HT level was negatively correlated with HAMD score （r = -0.572, P < 0.01）, whereas serum IL-6 level was positively correlated with HAMD score （r = 0.609, P < 0.01）. Serum 5-HT level was a protective factor, whereas serum IL-6 level was a risk factor for depression in AD patients （both P < 0.05）. The area under the ROC curve （AUC） for serum 5-HT level was 0.747, the sensitivity was 64.00%, and the specificity was 86.49%, respectively. The AUC of serum IL-6 level was 0.732, the sensitivity was 78.42%, and the specificity was 67.57%, respectively. The AUC constructed by combining serum 5-HT and IL-6 levels was 0.790, the sensitivity was 76.75%, and the specificity was 87.71%, respectively. Conclusions Abnormal serum 5-HT and IL-6 levels are correlated with depression in AD patients. These two combined can be used to predict the occurrence of depression in AD patients.