Because allelic polymorphism of the major histocompatibility complex class II antigens affects the immune response at several levels, we wished to characterize the contribution of a particular alpha or beta chain in vivo using transgenic mice. We have established and characterized 12 lines of H-2s/s mice carrying from 1 to 65 copies of an Ak beta transgene. The transgene was coexpressed with the endogenous allele in a tissue-specific manner, and Ak beta mRNA expression correlated well with transgene copy number. High copy number (extreme overexpression) of the transgene was associated with a variety of defects, including a significant reduction in Ia cell-surface expression, a severe decrease in B-cell number, abnormal extramedullary granulopoiesis, and an increased susceptibility to infection. In this paper we describe in detail the phenotype associated with high copy numbers of the Ak beta transgene. The defects we have observed may be relevant to similar phenomena seen in other transgenic mice. In addition, these mice have fortuitously provided a system in which to assess the effect of various levels of class II cell-surface expression in the thymus on selection of the T-cell repertoire.