The prothrombin time (PT) assay is the most clinically ordered coagulation test and is most often used for monitoring of vitamin K antagonist (VKA) therapy (e.g., warfarin), where results are expressed as an international normalized ratio (INR). The INR is in essence the patient's PT "mathematically adjusted" to a standardized value by taking into account the peculiarities of the test system through applying two "correction factors" defined by an international sensitivity index (ISI) and mean normal prothrombin time (MNPT). Although some manufacturers provide assigned ISI values for specific PT reagents and instrumentation, it is still recommended practice that laboratories check or locally validate these ISIs, as well as estimate the MNPT based on the population being tested. Where a manufacturer does not provide an ISI, the laboratory needs to define its own (local ISI) value. Current recommendations suggest the use of commercial reference-plasma calibration sets, but there is limited information to validate their performance in laboratory practice. We report our personal experience with use of some of these materials, as well as review alternate or supplementary procedures for calibration and/or validation of ISI and for determination and validation of MNPT. In brief, our data and experience suggests that further verification checks should be performed prior to acceptance of ISI and MNPT estimates generated from commercial reference-plasma calibration sets. We detail various strategies to ensure that laboratory practices are optimized to provide INRs that accurately reflect a patient's true anticoagulant status and to thus assist their clinical therapeutic management.