Cohort studies often compare the observed number of cases arising in a group under investigation with the number expected to occur on the basis of general population rates. The general population is taken to represent unexposed persons, but it is almost inevitably biased in that it comprises all types of people including exposed ones. To identify circumstances when this bias matters, the authors modeled its effect in relation to the size of the observed standardized mortality ratio (SMR) and the prevalence of exposed individuals in the general population. The authors found that bias may be a major problem, causing substantial underestimation of the true relative risk, when either the prevalence of exposure in the general population or the SMR are large. The bias can cause an apparent trend in SMRs with age when none exists. It also places a limit on the maximum size of the observed SMR, no matter how large the true relative risk. A table is provided showing the extent of bias in different circumstances. Cohort studies of people with common diseases or exposures, or that find large SMRs, when using general population expectations, need to consider the extent of bias from this source.