Metal ions generated from joint replacements are a cause for concern. There is no consensus on the best surrogate measure of metal ion exposure, and both serum and whole blood measurements are used in clinical practice. This study provides a guideline for interpretation of metal ion analysis in clinical practice. In a prospective trial comparing hip resurfacing (HR) with a conventional metal-on-metal (MoM) total hip arthroplasty (THA) cobalt and chromium levels were determined for whole blood and serum in 343 paired samples at regular intervals up to 24 months postoperatively. Cobalt whole blood and serum levels increased significantly after both procedures. Cobalt concentrations were significantly higher for the HR group compared to the THA group, at 3, 6 and 12 months, for whole blood and serum. At 24 months cobalt levels decreased and differences between HR and THA were no longer significant. In contrast, chromium whole blood levels remained significantly higher for HR until 24 months. Whole blood and serum levels could not be used interchangeably. The mean differences for cobalt and chromium between blood and serum values were +0.13 µg/L and -0.91 µg/L respectively. Regression analysis provided a formula for conversion from serum to blood of 0.34+[0.88*Co serum] for cobalt and 0.14 + [0.58*Cr serum] for chromium, with an acceptable prediction error below ±1.0 µg/L. Cobalt and chromium levels were significantly higher for HR versus THA, especially during the run-in phase of one year. Overall, the metal ion levels were well below 5 µg/L. We cannot recommend the use of whole blood over serum measurements or vice versa. The provided conversion formula between whole blood and serum in combination with the presented practical guidelines may be useful for clinical practice.