Epidemiologic studies have identified a number of lifestyle factors, e.g. diet, obesity, and use of certain medications, which affect risk of colon cancer. However, the magnitude and significance of risk factor-disease associations differ among studies. We propose that population trends of changing prevalence of risk factors explains some of the variability between studies when factors that change prevalence also modify the effect of other risk factors. We used data collected from population-based control who were selected as study participants for two time periods, 1991-1994 and 1997-2000, along with data from the literature, to examine changes in the population prevalence of aspirin and non-steroidal anti-inflammatory medication (NSAID) use, obesity, and hormone replacement therapy (HRT) over time. Data from a population-based colon cancer case-control study were used to estimate effect-measurement modification among these factors. Sizeable changes in aspirin use, HRT use, and the proportion of the population that is obese were observed between the 1980s and 2000. Use of NSAIDs interacted with BMI and HRT; HRT use interacted with body mass index (BMI). We estimate that as the prevalence of NSAIDs use changed from 10% to almost 50%, the colon cancer relative risk associated with BMI >30 would change from 1.3 to 1.9 because of the modifying effect of NSAIDs. Similarly, the relative risk estimated for BMI would increase as the prevalence of use of HRT among post-menopausal women increased. In conclusion, as population characteristics change over time, these changes may have an influence on relative risk estimates for colon cancer for other exposures because of effect-measure modification. The impact of population changes on comparability between epidemiologic studies can be kept to a minimum if investigators assess exposure-disease associations within strata of other exposures, and present results in a manner that allows comparisons across studies. Effect-measure modification is an important component of data analysis that should be evaluated to obtain a complete understanding of disease etiology.