A series of myoglobin active site analogues (1-6) has been synthesized and characterized. These synthetic models differ in their cavity dimensions, and have been designed to demonstrate the effects of steric factors on O-2 and CO binding affinities. Quantitative gas titrations were employed to measure these affinities, yielding M values that are strikingly lower than those reported for hemoglobin and myoglobin. The 1,4,7-triazacyclononane-capped porphyrin 1 has about 1200 times the CO affinity but only about 10 times the O-2 affinity of the cyclam-capped porphyrin 2, suggesting a more open gas binding cavity for 1. The cavity dimensions and conformation of 2 were determined by single-crystal X-ray structural analysis of the Zn analogue 7. This paper unequivocally demonstrates that steric effects can control the ratio of O-2/CO binding constants.