We have developed a sensitive, reliable and accurate procedure for estimating the base composition of small samples of DNAs. This method has been applied to the analysis of genomic DNAs from several sources including large regions of human DNA cloned as yeast artificial chromosomes. To determine whether the human genome is compartmentalized into large segments of homogeneous base composition, we examined the GC content of a 1.2 megabase contig spanning the cystic fibrosis gene.