ABSTRACT People with mosaicism for trisomy 21 have been shown to exhibit many of the same phenotypic traits present in people with non‐mosaic Down syndrome, but with varying symptom severity. However, the behavioral phenotype of people with mosaic Down syndrome (mDS) has not been well characterized. This study aimed to examine the prevalence of self‐report and caregiver‐report symptoms of depression and anxiety among a sample of 62 participants with mDS aged 12–46 and assess their association with the percentage of trisomy 21 in blood and/or buccal mucosa cells. The overall MANCOVA revealed a significant effect of trisomy on the set of internalizing scales, controlling for age and gender ( p = 0.038, partial eta 2 = 0.22). However, follow‐up univariate analyses showed that the initial significant effect of trisomy on fear ( p = 0.049, partial eta 2 = 0.08) did not survive correction for multiple comparisons (adjusted p = 0.300). No other effects were significant. This study highlights the high occurrence of depression and anxiety symptoms in individuals with mDS and the need for routine assessment to optimize their care. It also demonstrates the ability of people with mDS to complete these evaluations, thereby supporting their inclusion in research studies/clinical trials.