Down syndrome (DS) is the most common aneuploidy in liveborns with an estimated frequency of 1 in 650–1,000 births. Approximately 1–2% of all live-born DS individuals have mosaicism. The correlation between the percentage of mosaicism and the severity of the phenotype in mosaic trisomy 21 has been determined in previous studies. Patients with low percent of trisomy 21 have less phenotypic manifestations, higher IQs, and better overall survival. We report on a 1-day-old baby girl with subtle features of DS and low-level trisomy 21 mosaicism (8–13% in lymphocytes, 31% in buccal cells) with normal high resolution chromosome analysis. The aneuploidy was detected by 6.0 SNP microarray and confirmed by fluorescent in situ hybridization (FISH). Further studies to detect mosaicism are recommended from blood (using interphase FISH) or other tissues in the evaluation of a child with features of DS and a normal blood metaphase karyotype. SNP microarray technology appears to be a useful adjunct, being able to detect low-level mosaicism in these cases. © 2010 Wiley-Liss, Inc.