The autopsy is important to keep up the high quality of modern medicine, by giving clinicians feedback on diagnostics and therapies, and providing for medical training and medical research. Nevertheless, autopsy rates have been declining in many Western countries. From 1977 through 2011, the clinical autopsy rates in The Netherlands declined by 0.7% per calendar year, from 31.4% to 7.7%. In our hospital, the main reason for clinicians to not request autopsy and for next-of-kin to not allow autopsy was their assumption that autopsy would not show anything other than what was already known through pre-mortem diagnostics. Also, in 16.1% of cases, the next-of-kin feared for disfigurement of the deceased’s body. Therefore, autopsy methods should be developed that require less mutilation of the deceased’s body. According to the literature, a minimally invasive autopsy technique using imaging and biopsies usually performs better than non-invasive methods. We performed a prospective, single center, blinded cross-sectional study that compared the diagnostic performance of a minimally invasive autopsy (unenhanced whole-body CT and MRI scans, and image-guided biopsies) and conventional autopsy on 99 cases: the methods performed equally well. We found that post-mortem tissue biopsies were useful for molecular translational research; that our MRI scans combined with targeted heart-biopsies sufficed for establishing a cardiac cause of death; and that the post-mortem investigations diagnosed clinically unsuspected causes of death in 17% of the cases, emphasizing the necessity of performing post-mortems. In the future, for MIA to be implemented in clinical practice, radiologists need in-depth understanding of normal post-mortem processes for correct acquisition and interpretation of the post-mortem scans.