The aim of this paper is to review the most important methodological strengths and limitations of observational studies of humans, as opposed to experimental studies. The names “observational” and “experimental” go a long way in describing the differences. In an experimental study—that is, a randomised controlled trial (RCT)—the investigator experiments with the effect of the exposure by assigning exposure to a random sample of the study subjects. In an observational study, on the other hand, the investigator can only observe the effect of the exposure on the study subjects; he or she plays no role in assigning exposure to the study subjects. This makes observational studies much more vulnerable to methodological problems, so it is only reasonable that RCTs are considered the best way of proving causality.¹

One might ask why all studies are not experimental. First, not all research questions are suitable for an experimental design. Studies of diagnostics tests and treatment are highly suited, but studies of drug effects in pregnant women, or of the prognostic impact of diseases, are among the research questions that cannot be studied in an experimental design. Second, RCTs are often very expensive, in terms of both time and money, and an RCT may be conducted only after observational studies have failed to provide a clear answer to the research question. Observational studies give an idea about the incidence, prevalence, and prognosis of the disease that is studied, and this information is necessary for proper planning of the RCT. Often, the RCT will confirm what has been found in the preceding observational studies,^2,3 but occasionally the findings differ, or are even in the opposite direction, as in recent studies of the effect of hormone replacement therapy on cardiovascular risk.^4–6

Consequently, most research questions will be addressed in one …