Trialists argue about the usefulness of stratified randomization. For inves
tigators designing trials and readers who use them, the argument has create
d uncertainty regarding the importance of stratification In this paper, we
review stratified randomization to summarize its purpose, indications, acco
mplishments, and alternatives. In order to identify research papers, we per
formed a Medline search for 1966-1997. The search yielded 33 articles that
included original research on stratification or included stratification as
the major focus. Additional resources included textbooks. Stratified random
ization prevents imbalance between treatment groups for known factors that
influence prognosis or treatment responsiveness. As a result, stratificatio
n may prevent type I error and improve power for small trials (< 400 patien
ts), but only when the stratification factors have a large effect on progno
sis. Stratification has an important effect on sample size for active contr
ol equivalence trials, but not for superiority trials. Theoretical benefits
include facilitation of subgroup analysis and interim analysis. The maximu
m desirable number of strata is unknown, but experts argue for keeping it s
mall. Stratified randomization is important only for small trials in which
treatment outcome may be affected by known clinical factors that have a lar
ge effect on prognosis, large trials when interim analyses are planned with
small numbers of patients, and trials designed to show the equivalence of
two therapies. Once the decision to stratify is made, investigators need to
chose factors carefully and account for them in the analysis. J CLIN EPIDE
MIOL 52;1:19-26, 1999. (C) 1999 Elsevier Science Inc.