AbstractFentanyl passed rapidly into and out of erythrocytes to equilibrate with plasma concentration, and a red cell/plasma partition coefficient of 1.01 ± 0.0083 s.e.m. was found in 15 normal subjects. Most of the binding of fentanyl by red cells was by haemoglobin. 10% was bound by the cell membrane. Partition was unaffected by haematocrit, pH, or the concentration of fentanyl up to 0.5 mg ml−1 of blood. Dilution of plasma proteins, and replacement of plasma by buffer showed that uptake of fentanyl by red cells is a linear function of the concentration of free drug in plasma. A partition coefficient for red cells/buffer of 4.91 ± 0.032 s.e.m. was found. This relation was confirmed where binding to plasma proteins was altered in uraemia or hyperlipoproteinaemia, or by competitive displacement of fentanyl by aspirin and phenylbutazone thereby changing the size of the free fraction of fentanyl in plasma. Quinidine, however, inhibited the binding of fentanyl to plasma proteins and red cells equally, to maintain a partition coefficient of unity.