The aim of the present study is to test the susceptibility of chromosome 21 malsegregation in young mothers of Down syndrome children using combined micronucleus (MN) assay and FISH analysis. The present study included 62 Egyptian young mothers (age < 30 y) who were divided into 22 mothers of DS offspring and 40 age matched controls. All subjects were subjected to chromosomal analysis, micronucleus assay, and FISH analysis. High statistical significant difference was found between mothers of Down syndrome (MDS) and the controls in the MN percentage (P=0.034). Also there was high statistical significant difference between MDS and the controls in the percentage of positive malsegregation (P =0.0001). The specificity of combined MN% with FISH was 90%, while the sensitivity was 63.6%. Combined MN-FISH test is highly specific but moderately sensitive in assessing the risk of having children with DS in young mothers.