ObjectiveTo systematically review the current application status of the trial within cohort (TwiCs) design in clinical research, and to analyze the characteristics and methodological elements of existing TwiCs designs. MethodsA systematic literature search was conducted for TwiCs design from databases, and the basic characteristics of the trials as well as the design and implementation status of each trial were extracted. ResultsA total of 62 TwiCs trials were included. The disease fields with the most frequent application of this design were cancer, infectious diseases, mental and psychological disorders, etc. A majority of the studies adopted a phased informed consent model including broad informed consent and intervention-specific informed consent. Most of them did not consider the intervention refusal rate when estimating the sample size. In addition, intention-to-treat analysis was the main statistical analysis method used in current TwiCs designs, while a small number of studies adopted complier average causal effect analysis. ConclusionThe TwiCs design has broad application prospects, but its design is complex. When applying the TwiCs design in real-world settings, attention should be paid to designing reasonable informed consent strategies, sample size estimation, and statistical analysis methods based on the research context. In the future, a design and implementation framework for TwiCs should be established to guide researchers in different fields to conduct trials with this design.