Purpose Cytomegalovirus (HCMV) is a common viral infection that shapes lifelong immunity. A history of infection with HCMV has been associated with many chronic diseases, including cancer. In addition, prospective cohort studies have established that HCMV is associated with all-cause mortality. However, there are limited data regarding HCMV and cancer mortality. Methods Data were obtained from the National Health and Nutrition Examination Survey (NHANES) III study (1988–1994): subjects aged 18 to 98, who had HCMV serology results, did not report having cancer at baseline, and were eligible for mortality follow-up ( n  = 14,498). Mortality was ascertained until December 2011 using National Death Index (NDI) linkage. Results The unadjusted risk of all-cancer mortality was higher in HCMV seropositive individuals (HR 2.74, 95% CI 2.05–3.64). This association was attenuated after adjusting for age (HR 1.39, 95% CI 1.02–1.92), and other covariates (age, sex, race/ethnicity, smoking status, BMI, education, and C-reactive protein (CRP); HR 1.21, 95% CI 0.91–1.81). There was a statistically significant interaction between HCMV and sex ( p  = 0.01): HCMV seropositivity was associated with increased cancer mortality in men (HR 1.65, 95% CI 0.99–2.73) but not in women (HR 0.95, 95% CI 0.59–1.54). Conclusion(s) Consistent with prior reports, HCMV seropositivity may be associated with an increased risk of cancer-related mortality but the association is partially driven by socioeconomic status and other risk factors. Future research is needed to determine whether HCMV is a risk factor for cancer, as well as identify the specific cancer types where HCMV increases mortality.