We previously characterized Drosophila and human TAF subunits that make up the core TFIID complex found in all cells. Here, we report that differentiated B cells contain a novel substoichiometric TAF of 105 kDa not found associated with TFIID isolated from other cell types. The cDNA encoding hTAF(II)105 reveals a highly conserved C-terminal domain shared by hTAF(II)130 and dTAF(II)110, while the N-terminal coactivator domain has diverged significantly. All cells tested express TAF(II)105 mRNA, but only B cells contain significant levels of protein associated with TFIID. Transient overexpression of hTAF(II)105 selectively squelches the transcription of some genes in B cells. These properties suggest that TAF(II)105 is a cell type-specific subunit of TFIID that may be responsible for mediating transcription by a subset of activators in B cells.