<jats:sec><jats:title>Purpose</jats:title><jats:p> To compare short-course radiotherapy (RT) (4 Gy × 5) to longer-course RT (3 Gy × 10) for metastatic epidural spinal cord compression (MESCC). </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> Two-hundred three patients with MESCC and poor to intermediate expected survival were randomly assigned to 4 Gy × 5 in 1 week (n = 101) or 3 Gy × 10 in 2 weeks (n = 102). Patients were stratified according to ambulatory status, time developing motor deficits, and primary tumor type. Seventy-eight and 77 patients, respectively, were evaluable for the primary end point, 1-month overall response regarding motor function defined as improvement or no further progression of motor deficits. Other study end points included ambulatory status, local progression-free survival, and overall survival. End points were evaluated immediately after RT and at 1, 3, and 6 months thereafter. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> At 1 month, overall response rates regarding motor function were 87.2% after 4 Gy × 5 and 89.6% after 3 Gy × 10 (P = .73). Improvement rates were 38.5% and 44.2%, respectively, no further progression rates 48.7% and 45.5%, respectively, and deterioration rates 12.8% and 10.4%, respectively (P = .44). Ambulatory rates at 1 month were 71.8% and 74.0%, respectively (P = .86). At other times after RT, the results were also not significantly different. Six-month local progression-free survival was 75.2% after 4 Gy × 5 and 81.8% after 3 Gy × 10 (P = .51); 6-month overall survival was 42.3% and 37.8% (P = .68). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> Short-course RT with 4 Gy × 5 was not significantly inferior to 3 Gy × 10 in patients with MESCC and poor to intermediate expected survival. </jats:p></jats:sec>