Oxycodone is an opioid with strong analgesic effects widely used to treat acute and chronic pain. Interpretation of oxycodone concentrations in postmortem cases is complicated due to tolerance and overlapping concentrations for fatal and non-fatal levels. In this study, our aim was to develop and validate a method for oxycodone and its three metabolites: noroxycodone, oxymorphone, and noroxymorphone in postmortem femoral blood. Our goal was to define reference concentrations for intoxications and non-intoxications, and investigate metabolic ratios in different causes of death. A rapid LC-MS-MS method using protein precipitated postmortem blood was developed. LLOQ was 0.005 μg/g blood for all analytes, ULOQ was 1.0 μg/g for oxycodone and noroxycodone, and 0.25 μg/g for oxymorphone and noroxymorphone. The method displayed high precision (3.3-7.7%) and low bias (-0.3-12%). In total, 192 cases were analysed and concentrations ranged from 0.005-13 μg/g for oxycodone, 0.005-2.0 μg/g for noroxycodone, 0.005-0.24 μg/g for oxymorphone, and 0.005-0.075 μg/g for noroxymorphone. We found a significant difference in oxycodone concentration between the cases where oxycodone contributed and those where it did not. In spite of that, we do not recommend the use of a specific blood concentration to distinguish fatal intoxications. Instead, the percentiles from our dataset suggest that concentrations greater than 0.2 μg/g are likely to have contributed to toxicity, but that concentrations as high as 0.3 might be tolerated without toxic effects. In addition, we also found that a low noroxycodone/oxycodone ratio could point towards an acute fatal intoxication. In conclusion, the oxycodone concentration alone may not be sufficient to diagnose a fatal intoxication.