Background <p>Cefotaxime has been widely used in the clinical treatment of infections. However, there is still a lack of systematic researches for the adverse event profiles of cefotaxime through large-scale post-marketing monitoring.</p> Methods <p>This study investigated the adverse event profiles for cefotaxime in the Food and Drug Administration Adverse Event Reporting System database, delving into clinical characteristics, adverse event signals and variations in these signals across subgroups.</p> Results <p>Compared with Asia, Europe and America more commonly reported once-daily frequency. New severe hepatobiliary disorders were observed in neonates, children, or underweight elderly patients even when using adjusted doses below 1&#xa0;g. Significant variations in adverse event signals were identified in relation to continent, dose, onset time, and outcome.</p> Conclusions <p>The existence of non-recommended frequency in Europe and America warrants clinical attention when using cefotaxime. The identification of new severe hepatobiliary disorders highlights the critical need for personalized dosing strategies and intensified liver function monitoring for neonates, children, and elderly individuals with lower body weights. Furthermore, the differences in adverse event signals across subgroups underscore the necessity of developing targeted monitoring protocols. Further research is required to validate the association.</p> Clinical trial number <p>Not applicable.</p>