Background: Fatigue is the most common toxicity of all grade toxicities with regorafenib, was the second most common toxicity in the CORRECT (regorafenib monotherapy for previously treated metastatic colorectal cancer) study, and is a major reason for early dose modification. The results from a recent randomized study suggested that dexamethasone (DEX) can improve cancer-related fatigue. Patients and Methods: We retrospectively analyzed the effect of prophylactic use of an oral DEX on fatigue during regorafenib treatment in patients with metastatic colorectal cancer (mCRC). A total of 105 patients who had received regorafenib at our institution from May 2013 to August 2014 were divided into 2 groups according to oral DEX use (2 mg/day; at the physician's discretion). Results: Of the 105 patients, 31 received prophylactic DEX and 74 received regorafenib alone. The time to dose modification was significantly longer in the DEX group than in the no DEX group (15 days vs. 9 days; P = .009). The incidence of fatigue (grade >= 1) was significantly lower with DEX than without DEX (25.8% vs. 50.0%; P = .022). Fewer patients experienced a decreased appetite (grade >= 1; 3.2% vs. 35.1%; P <.001) and handefoot skin reaction (HFSR; grade >= 3; 3.2% vs. 25.7%, P = .002) with DEX than without DEX. Conclusion: DEX was effective in reducing fatigue during regorafenib treatment, resulting in prolonging the time to dose modification for regorafenib. The decreased incidence of appetite loss and HFSR also suggest that concurrent DEX administration with regorafenib warrants further investigation.