In the Eastern Central Mobile Belt of the Newfoundland Appalachians, late Precambrian basement inliers have εNd from −3 to +2, but Cambro-Ordovician metasedimentary rocks have initial εNd below −7. This region is inferred to have an "inverted" crustal residence structure, which influenced subsequent Appalachian-cycle magmatism. Ordovician and Silurian granitoid suites have εNd of −8 to −2, bracketing both basement and cover, but peraluminous, "S-type" granites have the lowest εNd. Devonian granites have initial εNd values from −5 to +1, and low εNd is associated with peraluminous character. These Paleozoic granites show geographic trends, with lowest εNd values in areas where metasedimentary rocks are abundant. They are suggested to contain anatectic material from both Precambrian basement and metasedimentary cover, but some "I-type" suites probably also include a mantle-derived component. In the adjacent Avalon Zone, Precambrian plutonic suites mostly have εNd from +1 to +6, but there are negative εNd values (−8 to −4) in the westernmost Avalon Zone. Devonian plutonic suites mostly have εNd from +2 to +5. Thus, the Precambrian crust of the Avalon Zone is largely "juvenile," except at its westernmost edge. Contrasts across the Eastern Central Mobile Belt–Avalon Zone boundary, defined by the Dover–Hermitage Bay fault system, indicate a major, crustal-scale structure, and suggest an isotopically distinct "central block" beneath the central Appalachian Orogen, rather than a simple extension of "Avalonian" crust. Similar geographic–isotopic patterns have been reported in Nova Scotia and New Brunswick, suggesting that this pattern represents a first-order deep-crustal subdivision of the northern Appalachian Orogen.