Blood gas transport was studied in unrestrained free-swimming cuttlefish, Sepia officinalis, following cannulations of an efferent branchial (arterial) vessel and the vena cava cephalica with indwelling catheters. In well-aerated water the arterial POO2 averaged about 100.00 mmHg and was fully saturated with O2. Mixed venous pOO2 varied between 17 and 40 mmHg, typically corresponding to blood O2 utilizations of 80% or higher. Some blood samples showed venous pH to exceed arterial, a tendency becoming more distinct during exposure to hypoxic water. The resulting higher O2 affinity of venous compared to arterial blood discourages O2 unloading in the tissues, while promoting efficient O2 loading in the gills. A high n-value of Sepia blood (n = 4.7) is important for maintaining a large arteriovenous O2 content difference and a high utilization of circulating O2.