In fluid membranes, mobile molecules are thought to collide at high frequencies. Concern has been expressed as to whether these colliding molecules are cross-linking during the chemical cross-linking of membrane molecules, thereby creating problems in interpreting such experiments. Hemoglobin was used as a model to test this possibility. Oligomers larger than the tetramer could be cross-linked depending on factors such as hemoglobin concentration, duration of the cross-linking reaction and the type of reagent. Under certain conditions, however, such as a hemoglobin concentration less than 150 microM or a duration of cross-linking shorter than 15 min, larger oligomers were not detectable. Analysis of these data suggests that the probability of random collisional cross-links under normal conditions is insignificant.