The CD8(+) T-cell response to infection involves a large initial expansion in the numbers of responding cells, accompanied by differentiation of these cells. Expression of the adhesion molecule CD62L is high on naïve cells and rapidly downregulated on the surface of the majority (approximately 90%) of cells during the 'effector' phase of acute infection. Adoptive transfer studies have been used to study differentiation in this system; however, relatively little work has investigated the phenotype of cells in the endogenous repertoire. We demonstrate that the extent of CD62L down-regulation is positively correlated with clone size in vivo, consistent with division-linked differentiation of responding cells. Other features of the endogenous CD62L(hi) and CD62L(lo) repertoire are that the CD62L(lo) repertoire is less diverse than the CD62L(hi) repertoire and represents a subset of clonotypes found in the CD62L(hi) repertoire. To test whether these observations are compatible with a mechanism of division-linked differentiation, we developed a mathematical model, where there is a probability of CD62L down-regulation associated with cell division. Comparison of model results with experimental data suggests that division-linked differentiation provides a simple mechanism to explain the relationship between clone size and phenotype of CD8(+) T cells during acute infection.