Soil organic matter is central to the soil health framework. Therefore, reliable indicators of changes in soil organic matter are essential to inform land management decisions. Permanganate oxidizable carbon (POXC), an emerging soil health indicator, has shown promise for being sensitive to soil management. However, strict standardization is required for widespread implementation in research and commercial contexts. Here, we used 36 soils—three from each of the 12 USDA soil orders—to determine the effects of sieve size and soil mass of analysis on POXC results. Using replicated measurements across 12 labs in the US and the EU (n = 7951 samples), we quantified the relative importance of 1) variation between labs, 2) variation within labs, 3) effect soil mass, and 4) effect of soil sieve size on the repeatability of POXC. We found a wide range of overall variability in POXC values across labs (0.03 to 171.8%; mean = 13.4%), and much of this variability was attributable to within-lab variation (median = 6.5%) independently of soil mass or sieve size. Greater soil mass (2.5 g) decreased absolute POXC values by a mean of 177 mg kg−1 soil and decreased analytical variability by 6.5%. For soils with organic carbon (SOC) >10%, greater soil mass (2.5 g) resulted in more frequent POXC values above the limit of detection whereas the lower soil mass (0.75 g) resulted in POXC values below the limit of detection for SOC contents <5%. A finer sieve size increased absolute values of POXC by 124 mg kg−1 while decreasing the analytical variability by 1.8%. In general, soils with greater SOC contents had lower analytical variability. These results point to potential standardizations of the POXC protocol that can decrease the variability of the metric. We recommend that the POXC protocol be standardized to use 2.5 g for soils <10% SOC. Sieve size was a relatively small contributor to analytical variability and therefore we recommend that this decision be tailored to the study purpose. Tradeoffs associated with these standardizations can be mitigated, ultimately providing guidance on how to standardize POXC for routine analysis.