Background Although the elderly population is increasing rapidly, little information is available regarding how the risk of postoperative mortality and morbidity increases when combined with age and comorbidity burden in patients undergoing musculoskeletal tumor surgery. Questions/purposes We evaluated the effect of age and comorbidity burden on the (1) postoperative complication rate and (2) in-hospital mortality rate after musculoskeletal tumor surgery. Methods We identified 5716 patients undergoing musculoskeletal tumor surgery during 2007 to 2012 using a Japanese national inpatient database. Logistic regression analyses were performed to examine the relationships of various factors with the rates of mortality and morbidity. Results The postoperative complication rate (6.7%) was associated with male sex (p = 0. The morbidity (21.6%; OR, 3.29; p \ 0.001) and mortality (4.1%; OR, 5.95; p \ 0.001) in patients 80 years or older with a Charlson Comorbidity Index of 4 or greater was increased three and six times, respectively, compared with patients 64 years or younger with no comorbidity. Conclusions We found that age and comorbidity burden together greatly increased the risk of morbidity and mortality. Our study showed quantitative evidence that will assist physicians in assessing perioperative risk accurately and provide a more informative explanation to elderly patients undergoing musculoskeletal tumor surgery. Level of Evidence Level IV, prognostic study. See the Instructions for Authors for a complete description of levels of evidence.