Background: Short-term steroids (< 2 weeks) have been used to alleviate fatigue in patients with advanced cancer. However, the efficacy and safety of long-term steroids (12 weeks) in patients with advanced cancer receiving palliative chemotherapy have not been studied. Methods: The study was an open-label, placebo-controlled, phase 3 RCT to evaluate the efficacy and safety of low dose dexamethasone (DEX) in reducing chemotherapy and cancer associated fatigue. Patients aged 18-60 years with performance status ≤2, undergoing palliative chemotherapy for advanced solid malignancies were randomized 1:1 to receive either DEX (4mg/day) or a placebo for 12 weeks. Fatigue was measured using the Symbolic Assessment of Fatigue Extent (SAFE) scale and EORTC FA12 scale, and QOL was assessed using the EORTC QLQ c30 at baseline, 6 weeks, and 12 weeks.The primary endpoint was to compare fatigue between the study arms at 6 weeks. Secondary endpoints were to compare fatigue at 12 weeks, QOL and toxicities. With a power of 80%, α of 5%, 126 patients (including 25% drop-outs) were required to show the superiority of DEX in reducing SAFE fatigue extent score by 50% at 6 weeks. Results: A total of 126 patients were randomized (64 in the placebo arm and 62 in the DEX arm) between Oct 2018-Sep 2022. The median age was 46.5 years and 67% were females. Metastatic breast (28%) and lung (16%) cancer were the common diagnosis. Twelve and 23 patients in the placebo arm and 13 and 22 patients in the DEX arm did not undergo week 6 and 12 assessment respectively due to disease progression. The results showed no significant differences in mean SAFE scores, FA12 scores, or QOL between the study arms at 6 and 12 weeks, except for higher FA12 social sequelae in the DEX arm at 12 weeks (P = 0.048) (Table). There were no significant differences in toxicities between the arms. Conclusions: The results of this study suggest that low-dose DEX is not effective in reducing chemotherapy associated fatigue or improving QOL in patients with advanced cancer. Clinical trial information: CTRI/2018/08/015222.