Objectives: To assess variation by EHR system in breaches of safety guidance around prescribing of ciclosporin, tacrolimus and diltiazem; to conduct user-interface research into the causes of such breaches. Design: A retrospective cohort study. Setting: Prescribing data in English primary care. Participants: English general practices and their respective electronic health records. Main outcome measures: The main outcome measures were (1) variation in ratio of breaching / adherent prescribing all practices (2) description of observations of EHR usage. Results: A total of 2,575,411 prescriptions were issued in 2018 for ciclosporin, tacrolimus and diltiazem (over 60mg); of these, 316,119 prescriptions breached NHS guidance (12.3%). Breaches were most common amongst users of the EMIS EHR (in 23.2% of ciclosporin & tacrolimus prescriptions, and 22.7% of diltiazem prescriptions); but breaches were observed in all EHRs. Conclusion: Design choices in EHR strongly influence safe prescribing of ciclosporin, tacrolimus and diltiazem; and breaches are prevalent in general practices in England. We recommend that all EHR vendors review their systems to increase safe prescribing of these medicines in line with national guidance. Almost all clinical practice is now mediated through an EHR system: further quantitative research into the effect of EHR design on clinical practice is long overdue.