We report findings from a term infant with persistent patency of the ductus arteriosus (PDA). His fetal tests had shown some ambiguity for trisomy 21. However, he did not show any of the frequently-seen phenotypic features associated with trisomy 21 in utero or after birth, and the postnatal karyotype was reported as normal. One of our team members decided to request for a repeat karyotype and he was then identified as a mosaic for this aneuploidy. These observations are potentially important because the proportion of affected cells could very well be a determinant of the phenotypic variability seen in infants with Down syndrome. Hence, mosaicism might need to be meticulously excluded in patients who are presented with only one or more phenotypic features associated with trisomy 21. In this report, we have briefly reviewed the need for evaluation in such infants; the diagnosis requires specific evaluation of in-vitro cultured blood lymphocytes from the patients, siblings, and parents for somatic and germinal trisomy 21 mosaicism. The mechanisms underlying the origin of trisomy 21 mosaicism are still unclear; embryonic meiotic errors such as nondisjunction and anaphase lag, and subsequent mitotic malsegregation may be responsible. Uniparental disomy needs investigation. In the absence of somatic recombination, postzygotic malsegregation in an originally unaffected, disomy 21 zygote could also be a cause. The incidence of this condition in the community might be higher than hitherto believed.