What causes heterogeneity in systematic reviews of controlled trials? First, it may be an artefact of the summary measures used, of study design features such as duration of follow-up or the reliability of outcome measures. Second, it may be due to real variation in the treatment effect and hence provides the opportunity to identify factors that may modify the impact of treatment. These factors may include features of the population such as: severity of illness, age and gender; intervention factors such as dose, timing or duration of treatment; and comparator factors such as the control group treatment or the co-interventions in both groups. The ideal way to study causes of true variation is within rather than between studies. In most situations however, we will have to make do with a study level investigation and hence need to be careful about adjusting for potential confounding by artefactual factors such as study design features. Such investigation of artefactual and true causes of heterogeneity form essential steps in moving from a combined effect estimate to application to particular populations and individuals. Copyright © 2002 John Wiley & Sons, Ltd.