More studies showed that diagnosis of cancer lead to occurrence of emotional problems in patient and his family. Fluoxetine is an anti-depression drug that used for treatment of Depression, Obsessive compulsive disorder, Panic disorder and nervous incontinence. The aim of this study was investigate the effect of fluoxetine on quality of life in patients with solid cancers. This is a randomized controlled clinical trial that has been done on two groups of patients each with 70 patients. One group received fluoxetine for 12 weeks and another group received placebo. In baseline and end of study, SF36 questionnaire were completed for all patients and results analyzed by statistical methods in SPSS.16. The most prevalent malignancy in case and control groups was gastric cancer with 40% and 42.9%, respectively. There wasn’t significant difference in QOL of patients in baseline between two groups but in the end of study, emotional-psychological health and vitality scores in case group was better than control group. In terms of physical symptoms and depression, the case group was better than control group. In start and end of study, in QOL score only difference was seen in physical activity which was better in case group than control group. Results showed that fluoxetine prescription in patients could recovery some dimensions of QOL and general health but not effect on some dimensions which probably related to short duration of fluoxetine prescription in patients.