The random-zero and standard mercury sphygmomanometers are used frequently, and sometimes interchangeably, in epidemiologic studies. To determine whether there is a systematic difference between them, the authors measured systolic, fourth-phase, and fifth-phase diastolic blood pressures using both sphygmomanometers simultaneously in a series of six experiments. For most experiments, the system for simultaneous blood pressure measurements employed one cuff connected to both sphygmomanometers, which were carefully calibrated and read by two trained technicians using a double stethoscope. Order of use of the random-zero sphygmomanometer was randomly assigned, and technicians were blind to each others readings. At deflation rates of 2 mmHg/second, readings of the random-zero sphygmomanometer were systematically lower than those of the standard mercury sphygmomanometer −0.9 mmHg for systolic, −1.8 mmHg for fourth-phase, and −1.8 mmHg for fifth-phase diastolic blood pressures (all differences, p<0.001). The difference persisted after adjustment for subject age, sex, heart rate, blood pressure level, observer, and room temperature, and was present for varying deflation rates. However, by draining the residual mercury from a random-zero sphygmomanometer and using the instrument as if it were a standard mercury sphygmomanometer, much of the difference between the two was eliminated. This suggests that the mechanism for the difference relates to the increased height of mercury in the random-zero manometer tube. The authors conclude that the random-zero and standard mercury sphygmomanometers should not be used interchangeably in epidemiologic studies.