Nucleated red blood cells (nRBCs) are not identified in the peripheral blood in healthy individuals beyond the neonatal period. Their presence in children and adults is traditionally considered pathologic. Contemporary hematology analyzers measure nRBCs at very low levels compared to traditional manual morphometric methods. The original launch of the Sysmex XN analyzer in this study’s clinical laboratory verified the previously used nRBC reference interval of 0.00 to 0.01 × 106/μL. However, nRBC results from apparently healthy patients were flagged as abnormal (high), subsequently causing patient anxiety and increased subspecialty referrals.


To determine whether current reference intervals (RIs) for nRBCs were clinically relevant.


We performed a prospective analysis of 405 300 specimens from nonhospitalized individuals who received a complete blood count. Applying inclusion/exclusion criteria produced a total specimen pool of 66 498.


Of the 66 498 samples with otherwise normal complete blood count results from healthy, nonhospitalized individuals, 338 showed results outside the previously established RI; 336 of 66 498 (0.5%) had nRBC results greater than 0.01 × 106/μL. Two samples had nRBC values greater than 0.10 ×106/μL.


Based on statistical analysis of our results, we concluded that the upper limit of the RI could be updated from 0.01 × 106/μL to 0.10 × 106/μL. Increasing the upper limit of normal for the nRBC RI should decrease patient consternation from an abnormal laboratory value and significantly decrease costs through reducing unnecessary follow up care, and without causing patient harm.

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Author notes

The authors have no relevant financial interest in the products or companies described in this article.

Portions of this paper were presented at the College of American Pathologists 2021 annual meeting on September 26, 2021; virtual.