Writing an informed consent form (ICF) for biomedical research is a difficult task. We conducted a multicenter single-blind randomized controlled trial to identify whether a working group or the systematic improvement in lexico-syntactic readability or an association of the two could increase the comprehension of the written information given to healthy volunteers enrolled in biomedical research. Participants were randomized to read one of four versions of the ICF: unchanged ICF (A), ICF with systematic lexico-syntactic readability improvement (B), ICF modified by a working group (C), and ICF modified by the working group followed by systematic lexico-syntactic improvement (D). The primary end-point was the objective comprehension score at day 0 for each study group. The scores of objective comprehension at day 0 were statistically different between the four study groups (anovaP = 0.020). The pairwise analysis showed an improvement in the working group vs. the unchanged group (P = 0.003), and a tendency to improvement in the group who read the ICF modified using lexico-syntactic readability and in the group who read the ICF modified using the two methods (P = 0.020 and 0.027 respectively). We conducted a two-way anova to identify some characteristics of the population which could explain this score. There was a significant interaction between the type of informed consent document (ICD) and the gender. Improving the ICD in phase I biomedical research leads to better comprehension, whether the method used is systematic lexico-syntactic improvement or a review by a working group. The improvement is specifically observed in men compared with women. Conversely, while both methods diverge in their effect on lexico-syntactic readability, their association is not mandatory. We suggest that in all phase I clinical trials, the ICF be improved by either method.