This study examines the influence of familiarity on witnesses’ memory and the individual effectiveness of each of the four cognitive interview instructions in improving witnesses’ recall of scripted events. Participants (N = 195), either familiar or unfamiliar with the hospital script, were presented with a video of a surgical operation. One week later, an interviewer used one of the four cognitive interview instructions or a control instruction to ask them about the video. Participants familiar with the surgery context recalled significantly more correct information and, in particular, more consistent and irrelevant details than those unfamiliar with the surgery context. Furthermore, the results confirmed the effectiveness of all four cognitive interview mnemonics in enhancing the amount of correct information reported, irrespective of the participants’ familiarity with the critical event. However, their efficacy differed depending on the category of details considered. The practical implications of these results are discussed.