Upcoming measurements of the 21-cm line of neutral hydrogen will open a new observational window into the early stages of structure growth, providing a unique opportunity for probing large-scale cosmological signatures using the small-scale signals from the first stars. In this paper we evaluate the detection significance of compensated isocurvature perturbations (CIPs) from observations of the 21-cm hydrogen-line during the cosmic-dawn era. CIPs are modulations of the relative baryon and dark-matter density that leave the total matter density unchanged. We find that, under different assumptions for feedback and foregrounds, the ongoing HERA and upcoming SKA1-low experiments will provide constraints on uncorrelated CIPs at the level of $sigma(A_{rm CIP})= 10^{-3}-10^{-4}$, comparable to the sensitivity of upcoming CMB experiments, and potentially exceeding the constraints from cosmic-variance limited BAO surveys.
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