Introduction: Most patient safety research has focused on specialist-care settings where there is an appreciation of the frequency and causes of medical errors, and the resulting burden of adverse events. There have, however, been few large-scale robust studies that have investigated the extent and severity of avoidable harm in primary care. To address this, we will conduct a 12-month retrospective cross-sectional study involving case note review of primary care patients. Methods and Analysis: We will conduct electronic searches of general practice (GP) clinical computer systems to identify patients with avoidable significant harm. Up to sixteen general practices from three areas of England (East Midlands, London and the North West) will be recruited based on practice size, to obtain a sample of around 100,000 patients. Our investigations will include an ‘enhanced sample’ of patients with the highest risk of avoidable significant harm. We will estimate the incidence of avoidable significant harm and express this as ‘per 100,000 patients per year’. Univariate and multivariate analysis will be conducted to identify the factors associated with avoidable significant harm. Ethics/Dissemination: The decision regarding participation by general practices in the study is entirely voluntary; the consent to participate may be withdrawn at any time. We will not seek individual patient consent for the retrospective case note review, but if patients respond to publicity about the project and say they do not wish their records to be included we will follow these instructions. We will produce a report for the Department of Health’s Policy Research Programme and several high-quality peer-reviewed publications in scientific journals. The study has been granted a favourable opinion by the East Midlands Nottingham 2 Research Ethics Committee (reference 15/EM/0411) and Confidentiality Advisory Group approval for access to medical records without consent under section 251 of the NHS Act 2006 (reference 15/CAG/0182).