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Only a minimum generally can be placed on the size of oligomers formed by G protein-coupled receptors. Attempts to obtain an explicit estimate have not been persuasive, owing in part to their reliance on questionable models. We therefore have developed a quantitative method based on fluorescence resonance energy transfer (FRET), which we have applied to oligomers of M2 receptors tagged at the N-terminus with enhanced green or yellow fluorescent protein (eGFP-M2 or eYFP-M2) and co-expressed in Chinese hamster ovary cells. The approach is based on the relationship between apparent FRET efficiency and the ‘pair-wise’ FRET efficiency (E) between a single donor and a single acceptor in an oligomer of specified size (n). Emission spectra were analyzed by spectral deconvolution, and apparent efficiencies were measured by donor-dequenching and acceptor-sensitized emission at different ratios of eYFP-M2 to eGFP-M2. The data were interpreted in terms of a model that considers all combinations of donor and acceptor within the oligomer to obtain fitted values of E as follows: n=2, 0.473±0.011; n=4, 0.206±0.009; n=6, 0.132±0.005; n=8, 0.100±0.002. The pair-wise FRET efficiency determined independently by fluorescence lifetime imaging was 0.206. The M2 receptor therefore can be identified as a tetramer, in agreement with the results of a parallel study in which the oligomeric size has been estimated from FRET efficiencies measured at the level of single pixels.