Methyl methacrylate (MMA), a volatile liquid used to make dentures, hearing aids, joint prostheses, and medical adhesives, has been associated with colorectal carcinomas in acrylic sheet manufacturing workers. A case-control proportionate cancer mortality investigation was conducted to determine cancer death differences in orthopedic surgeons performing total joint replacements (TJRs) (MMA-exposed cases) and general surgeons not performing TJRs (unexposed controls). The American Colleges of Orthopedic Surgeons and General Surgeons provided complete demographic information on 468 male orthopedic surgeons and 1,890 male general surgeons who died during 1991-2001. Decedent data was submitted to the National Death Index for matching with underlying causes of death on state death certificates. Proportionate differences in ages at death, deaths from cancer, and deaths from site-specific cancers were analyzed for statistically significant differences by unpaired, two-tailed t tests for continuous variables and by both proportionate cancer mortality ratios and Yates-corrected chi squares for categorical variables. Orthopedic surgeons died of cancer more often (χ (2) = 7.699, P = 0.006) and at younger (t = 5.53, P < 0.001) ages (mean = 69.4 years) than general surgeons (mean = 79.2 years). For site-specific cancers, orthopedic surgeons died of esophageal cancer (χ (2) = 4.372, P = 0.037) and myeloproliferative malignancies (χ (2) = 4.369, P = 0.037) more often than general surgeons. Orthopedic surgeons are chronically exposed to MMA and are proportionately more likely to die from cancer, especially esophageal and myeloproliferative cancers, than general surgeons. MMA-exposed healthcare workers may be at increased risks of untimely deaths from site-specific malignancies.