Background: Cancer-related fatigue (CRF) significantly impacts QoL of patients. Dexamethasone with physical activity may improve CRF. Methods: Phase III randomized study in patients with advanced cancer on palliative intent therapy, with ECOG PS 0-2, and fatigue score > 4/10 on numeric rating scale. Intervention included oral dexamethasone 8 mg twice daily for 7 days, and exercise (aerobic + resistance). Results: From Dec 2022 to Feb 2023, we enrolled 114 pts; 56 in intervention arm, and 58 in standard arm. Median age was 56 yrs (IQR, 47.8 to 65), with 74 (64.9%) males. Common tumors were lung (75, 65.8%), head-and-neck (12, 11%), and breast (10, 8.8%). Compliance was 87.3% (n=48) for dexa, and 70.9% (n=39) for exercise. Primary endpoint of mean improvement in FACIT-Fatigue subscale on day 8 was 3.22 (SD, 12.69) in intervention, compared to 1.73 (SD, 9.97) in standard arm; P =0.495. However, 54.5% patients in intervention had at least 3 points (minimal clinically relevant) decrease in fatigue, vs 41.8% in control; P=0.182. By day 29, mean change in FACIT-Fatigue scores compared to baseline was similar in intervention vs control; 2.61 (SD, 14.64) vs 2.68 (SD, 12.87), respectively; P=0.978. Although overall symptoms (ESAS) and general QoL were similar, there was a significant improvement in fatigue symptom on EORTC QLQ-C30 in intervention on day 29 compared to baseline; P=0.013. Sleep quality also significantly improved on Day 29 in intervention; P=0.018. On EORTC-QLQ FA12 (cancer-related fatigue QoL), physical fatigue improved significantly from baseline to Day 8 in intervention versus control; P=0.035; with no difference in emotional or cognitive fatigue, interference with daily life, or social sequelae. There was no difference in grade ≥ 3 adverse events between groups; 18 (32.7%) in intervention group versus 18 (30.5%) in control group; P=0.799. Conclusions: Dexamethasone and exercise did not lead to a statistically significant improvement in fatigue by FACT-Fatigue scale, although it resulted in greater proportion of pts with clinically relevant improvements in fatigue. The intervention significantly improved QoL fatigue symptom score and reduced physical fatigue on QoL, along with improving sleep quality. Clinical trial information: CTRI/2022/09/045678.