The TSH receptor (TSHR), a heptahelical G protein coupled receptor on the surface of thyrocytes, is a major autoantigen and physiologic regulator of the thyroid gland. Unlike other G protein coupled receptors (GPCRs), the TSHR undergoes post-translational cleavage of its ectodomain leading to the existence of several forms of the receptor on the plasma membrane. We previously hypothesized that in order to achieve high fidelity and specificity of TSH ligand or TSHR-autoantibody signaling, the TSHR may compartmentalize into microdomains within the plasma membrane. In support of this hypothesis we have shown previously that TSHRs reside in GM₁ enriched lipid rafts in the plasma membrane of TSHR expressing cells. In this study, we further explore the different forms of TSH receptors which reside in lipid rafts. We studied both TSHR transfected cells and rat thyrocytes, using both non-detergent biochemical analyses and receptor-lipid raft co-localization. Using the biochemical approach we observed that monomeric receptors existed in both raft and non-raft fractions of the cell surface in the steady state. We also demonstrated that the multimeric forms of the receptor were preferentially partitioned into the lipid microdomains. Different TSHR forms, including multimers, were dynamically regulated both by receptor specific and post receptor specific modulators. TSH ligand and TSHR-antibody of the stimulating variety induced decrease of multimeric forms in the raft fractions. In addition, multimeric and monomeric forms of the receptor were both associated with Gs within and outside of the rafts. Although failure to achieve total lipid raft disruption prevented a conclusion regarding the relative power of TSHR signaling within and without the raft domains, these data showed clearly that not only were a significant proportion of TSHRs residing within lipid microdomains but that constitutive multimerization of TSHRs was actually regulated within the lipid rafts.