In England and Wales there is a conflict between the law and advice from regulatory bodies in relation to the sampling of human tissue for histological examination following medico-legal post-mortem examinations. Considering the results of previous publications, we performed a specific study to investigate the role of histology in determining the cause of death in cases at a forensic unit. A retrospective study of 500 adult forensic cases was performed. Cases were categorized by the role the histological examination played in determining a cause of death and its contributory factors. Furthermore, cause of death, manner of death, organ systems involved, and discrepancies were assessed. Of the 500 cases, histology was undertaken in 287 cases (58 %). Microscopic examination provided the cause of death in 2 % of cases where histology had been undertaken, and it added to the cause of death in 8 %. In 61 % of cases microscopy confirmed the macroscopic findings, and in 30 % it did not influence the medical cause of death. Histological examination of all organs in all forensic cases for the purpose of providing a medical cause of death is not supported. Practice guidance should be adjusted to reflect that, while histological examination is essential in certain circumstances, the decision to retain material for histology should be made on a case by case basis at the pathologist's discretion.