A vaccine, claimed to be effective against preventing a particular disease, is usually approved on the basis of the results from the three phases of clinical trials. The Phase III trial of a vaccine is primarily focused on detecting the extent to which the vaccine is effective in preventing the disease. The effectiveness of the vaccine is usually measured by means of protective vaccine efficacy ( V E). Estimating this V E, under both cohort and case–control design, is one of the primary concerns in vaccine studies. This chapter gives a brief overview of how V E is defined and estimated under various circumstances.