By methods analogous to those used in the classical statistical analysis of bacterial mutation, we have analyzed the formation of plasmid-free cells in populations of Escherichia coli harboring pBR322-derived plasmids. Application of fluctuation tests and papilla analysis suggested that there is a high variance in the probability that a plasmid-containing cell will produce a plasmid-free daughter cell. Apparently a subpopulation of plasmid-containing cells gives rise to progeny that produces plasmid-free cells with a high and unpredictable rate. This finding raises the question of whether plasmid maintenance can be adequately described by the conventional mathematical models.