Autoimmune safety evaluation is an important component of post-licensure vaccine safety evaluation. Recently, we published the findings from a large observational safety study of the quadrivalent human papillomavirus vaccine in females. From this study, based on two large managed care organizations, we have obtained some empirical data that may prove useful for the design of future vaccine safety studies within a managed care environment. For autoimmune conditions, a major challenge in vaccine safety study is to determine true incident cases in relation to the timing of vaccination. We found expert case review of medical records an indispensable component for autoimmune safety studies based on electronic health records. Case identification should also be expanded to include the use of laboratory test results or other relevant measures in addition to the disease specific ICD-9 diagnosis codes, when applicable. Furthermore, we recommend the parallel use of both safety signal evaluation that involves pattern evaluation for conditions that are more common, and statistical comparisons for conditions that are rather rare. Finally, we recommend an accompanying vaccine uptake study to understand the potential selection bias and confounding in a given study population that should be addressed with data collection and analytical techniques.