Most studies of preventative vaccines aim to enroll study populations in which the majority of subjects are naïve for the disease targeted by the vaccine. Occasionally, preventative vaccines must be studied in older populations consisting of a large proportion of subjects who are not naïve to the disease. In such situations, it is sometimes not practical to screen subjects for a history of the disease and restrict enrollment to only naive subjects. Also, there may be public health value in estimating the vaccine's impact in the general population including both naïve and non-naïve subjects. Interpretation of efficacy analyses in the general population, however, can present challenges. These challenges will be discussed. An example from a GARDASIL® vaccine study will be presented along with a nonproportional hazards model which can be applied to assist in interpretation of the data.