A quantitative assessment has been made of the interaction between exchangeable mimics of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and cholesterol in the liquid-ordered (l(0)) and the liquid-disordered (l(d)) states using the nearest-neighbor recognition (NNR) method. This assessment has established that these lipids mix ideally in the l(0) phase (i.e., they show no net attraction or repulsion toward each other) but exhibit repulsive interactions in the l(d) phase. The implications of these findings for the interactions between unsaturated phospholipids and cholesterol in eukaryotic cell membranes are briefly discussed.