Background. Although essential to guide control measures, published estimates of influenza-related seasonal mortality for low- and middle-income countries are few. We aimed to compare influenza-related mortality among individuals aged ⩾65 years in South Africa and the United States. Methods. We estimated influenza-related excess mortality due to all causes, pneumonia and influenza, and other influenza-associated diagnoses from monthly age-specific mortality data for 1998–2005 using a Serfling regression model. We controlled for between-country differences in population age structure and nondemographic factors (baseline mortality and coding practices) by generating age-standardized estimates and by estimating the percentage excess mortality attributable to influenza. Results. Age-standardized excess mortality rates were higher in South Africa than in the United States: 545 versus 133 deaths per 100,000 population for all causes (P < .001) and 63 vs 21 deaths per 100,000 population for pneumonia and influenza (P=.03). Standardization for nondemographic factors decreased but did not eliminate between-country differences; for example, the mean percentage of winter deaths attributable to influenza was 16% in South Africa and 6% in the United States (P < .001). For all respiratory causes, cerebrovascular disease, and diabetes, age-standardized excess death rates were 4—8-fold greater in South Africa than in the United States, and the percentage increase in winter deaths attributable to influenza was 2—4-fold higher. Conclusions. These data suggest that the impact of seasonal influenza on mortality among elderly individuals may be substantially higher in an African setting, compared with in the United States, and highlight the potential for influenza vaccination programs to decrease mortality.