Comparative effectiveness research – the conduct and synthesis of systematic research in order to compare the benefits and harms of alternative treatment options – is of critical importance in enabling informed health care decisions to be made. This user-friendly, practical handbook examines in depth how best to perform such comparative effectiveness research. A wide range of topics and methods are discussed, including research synthesis, sampling analysis, assessment of evidence design, systematic evaluation of statistical analysis, and meta-analysis. The discussion extends well beyond the fundamentals by encompassing “complex” systematic reviews, “cumulative” meta-analyses, and logic-based versus utility-based decision making. Health care providers, researchers, instructors, and students will all find this to be an invaluable reference on the compelling current issues and important analytical tools in comparative effectiveness research.