The molecular conformation of the halogen-free thyroid hormone analogue, N-acetyl-4'-methoxy-3,5,3'-trimethyl-L-thyronine ethyl ester, has beeen determined by X-ray diffraction techniques. The observed molecular conformation is similar to that found for the natural hormone 3,5,3'-triiodo-L-thyronine (T3). In this structure, the 3'-methyl group is distal, the overall conformation is cisoid, and the diphenyl ether conformation is twist--skewed. These structural similarities with T3 show that the conformation features required by the active hormone can still be maintained with methyl substitution. The observation that the halogen-free analogues have relatively high activity but extremely low protein binding affinity implies that the role of iodine in hormone transport and biological activity can be deifferentiated. These data suggest that the iodines enhance hormone--protein binding by virtue of their electronic, as well as steric, properties.