Cytogenetic expression of the fragile site at Xq27.3 is only found in those patients who have a full mutation of the FMR1 gene, i.e., a large amplification of the CGG repeat. However, an expansion of this repeat, although necessary, does not seem to be sufficient to cause expression of fra (X)(q27.3). Other factors are clearly needed, e.g., thymidylate stress. Little or no attention has been paid to the possible role of histones in the expression of the fragile sites, in spite of their structural and regulatory role in the chromatin complex. Histones can be modified by treating intact cells in vitro with butyrate, a substance that causes histone acetylation. The purpose of the present work is to test the effect of butyrate and of the acetylating compound acetyl‐L‐carnitine on the expression of fra (X)(q27.3) by treating peripheral lymphocytes of fragile X syndrome patients with these substances in vitro. we show that this treatment causes a significant inhibition of fra (X)(q27.3) expression. © 1994 Wiley‐Liss, Inc.