Rats exposed to inhaled toxicants while in plethysmographs having nose or neck seals may breathe against a negative pressure gradient during exposure. Breathing against negative pressure might affect the respiratory pattern and thus, the uptake or deposition of toxicant. The respiration of 10 conscious rats restrained in plethysmographic nose-only inhalation exposure tubes having a neck seal, was measured during breathing against ambient, negative and positive pressures (0 to +/- 7.5 cm H2O). Negative pressure increased respiratory frequency and reduced tidal volume, but minute volume was little changed. The estimated fraction of inspirate reaching the alveoli was reduced and inspiratory flow was increased. The magnitudes of these changes were small at typical exposure pressures, and the magnitudes of their effects on uptake and deposition would be expected to fall within the range of normal intersubject variability. Positive pressure tended to have effects opposite those of negative pressure.