BACKGROUND: The number of smoking-attributable deaths is commonly estimated using current and former smoking prevalences or lung cancer mortality as an indirect metric of cumulative population smoking. Neither method accounts for differences in the timing with which relative risks (RRs) for different diseases change following smoking initiation and cessation. We aimed to develop a method to account for time-dependent RRs. METHODS: We used birth cohort lung cancer mortality and its change over time to characterize time-varying cumulative smoking exposure. We analyzed data from the American Cancer Society Cancer Prevention Study II to estimate RRs for disease-specific mortality associated with current and former smoking, and change in RRs over time after cessation. RESULTS: When lung cancer was used to measure cumulative smoking exposure, 254,700 male and 227,000 female deaths were attributed to smoking in the US in 2005. A modified method in which RRs for different diseases decreased at different rates after cessation yielded similar but slightly lower estimates [251,900 (male) and 221,100 (female)]. The lowest estimates resulted from the method based on smoking prevalence [225,800 (male) and 163,700 (female)]. CONCLUSIONS: Although all methods estimated a large number of smoking attributable deaths, future efforts should account for temporal changes in smoking prevalence and in accumulation/reversibility of disease-specific risks.