Background The cluster randomized crossover (CRXO) design is gaining popularity in trial settings where individual randomization or parallel group cluster randomization is not feasible or practical. In a CRXO trial, not only are clusters of individuals rather than individuals themselves randomized to trial arms, but also each cluster participates in each arm of the trial at least once in separate periods of time. We will review publications of clinical trials undertaken in humans that have used the CRXO design. The aim of this systematic review is to summarize, as reported: the motivations for using the CRXO design, the values of the CRXO design parameters, the justification and methodology for the sample size calculations and analyses, and the quality of reporting the CRXO design aspects. Methods/Design We will identify reports of CRXO trials by systematically searching MEDLINE, PubMed, Cochrane Methodology Register, EMBASE, and CINAHL Plus. In addition, we will search for methodological articles that describe the CRXO design and conduct citation searches to identify any further CRXO trials. The references of all eligible trials will also be searched. We will screen the identified abstracts, and retrieve and assess for inclusion the full text for any potentially relevant articles. Data will be extracted from the full text independently by two reviewers. Descriptive summary statistics will be presented for the extracted data. Discussion This systematic review will inform both researchers addressing CRXO methodology and trialists considering implementing the design. The results will allow focused methodological research of the CRXO design, provide practical examples for researchers of how CRXO trials have been conducted, including any shortcomings, and highlight areas where reporting and conduct may be improved.