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Background  Randomized pre-post designs, with outcomes measured at baseline and after treatment, have been commonly used to compare the clinical effectiveness of two competing treatments. There are vast, but often conflicting, amount of information in current literature about the best analytic methods for pre-post designs. It is challenging for applied researchers to make an informed choice.    Methods  We discuss six methods commonly used in literature: one way analysis of variance (“  ANOVA”   ) , analysis of covariance main effect and interaction models on the post-treatment score (“  ANCOVA   I ” and “  ANCOVA   II ”),   ANOVA   on the change score between the baseline and post-treatment scores (“  ANOVA-Change  ”), repeated measures (“  RM”  ) and constrained repeated measures (“  cRM”  ) models on the baseline and post-treatment scores as joint outcomes. We review a number of study endpoints in randomized pre-post designs and identify the mean difference in the post-treatment score as the common treatment effect that all six methods target. We delineate the underlying differences and connections between these competing methods in homogeneous and heterogeneous study populations.    Results    ANCOVA   and   cRM   outperform other alternative methods because their treatment effect estimators have the smallest variances.   cRM   has comparable performance to   ANCOVA   I  in the homogeneous scenario and to   ANCOVA   II  in the heterogeneous scenario. In spite of that,   ANCOVA   has several advantages over  cRM:  i) the baseline score is adjusted as covariate because it is not an outcome by definition; ii) it is very convenient to incorporate other baseline variables and easy to handle complex heteroscedasticity patterns in a linear regression framework.    Conclusions    ANCOVA   is a simple and the most efficient approach for analyzing pre-post randomized designs.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12874-021-01323-9.

Statistical analysis of two arm randomized pre-post designs with one post-treatment measurement