Histone deacetylase (HDAC) inhibitors have been demonstrated to regulate myeloid cell differentiation. In the present study the effects of the HDAC inhibitor trichostatin A (TSA) on the tetraspanin cell surface antigen CD9 were determined in primary murine macrophages. TSA inhibited CD9 protein and message expression and was optimal by 48h. TSA did not induce similar effects on other surface markers and resulted in a modest increase or no effect on CD54 and CD11b, respectively. These effects were concentration dependent and concomitant with increased histone H4 acetylation. While interferon-γ (IFN-γ) and TSA had similar effects on CD9 expression, transcriptional profiling demonstrated significant differences in the genes activated by these stimuli. Notably CD14 message was down-regulated by IFN-γ while increased by TSA. These results demonstrate that HDAC inhibition may modulate macrophage function in part through changes in the expression of membrane proteins associated with matrix interactions.