The Skaergaard intrusion of East Greenland is one of the best studied layered intrusions on Earth and preserves an exceptional rock record produced during low-pressure, closed-system crystallization of Fe-rich tholeiitic magma. The lead isotope compositions of plagioclase feldspar in cumulates and related igneous rocks of the Skaergaard intrusion were determined directly from single spot analyses in thin section by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) (n = 757). Plagioclase primocrysts, typically with <2 ppm Pb, and feldspar in interstitial pockets from the Layered Series and from most of the Marginal Border Series have the same Pb isotope compositions within analytical uncertainty (208Pb/206Pb = 2.20 ± 0.06; 207Pb/206Pb = 0.889 ± 0.028). There are no significant Pb isotope differences between cores and rims of individual plagioclase primocrysts or between different types of interstitial pockets (e.g., interstitial granophyre, symplectites). These Pb isotope compositions are less radiogenic than those from most of the contemporaneous East Greenland flood basalts indicative of crustal contamination at deeper crustal levels prior to emplacement. Plagioclase from three samples of the Marginal Border Series adjacent to host gneisses (<5 m from the contact) have higher 208Pb/206Pb (2.30 ± 0.06, 2.35 ± 0.02, 2.51 ± 0.21) compared to the rest of the intrusion. These results confirm that crystallization of the Skaergaard intrusion occurred under essentially closed-system conditions with localized minor incorporation of “amphibolitic” gneiss. Hydrothermal alteration occurred at near-solidus to subsolidus conditions by circulating meteoric fluid that had equilibrated with the overlying flood basalts. This alteration resulted in albitized interstitial granophyre and rare spot analyses from plagioclase primocrysts characterized by Pb isotope compositions comparable to those of the flood basalts. Granophyres of different origins (e.g., transgressive granophyre, granophyric segregation) have variable Pb isotope compositions (208Pb/206Pb = 2.09–2.51; 207Pb/206Pb = 0.844–1.013) that are distinct from the Skaergaard cumulates. Based on Pb isotope systematics, combined with published SrNd isotopic compositions and 40Ar/39Ar geochronology from East Greenland and Faroe Island basalts, the Skaergaard intrusion is linked to eruption of the earliest of the Plateau Basalts in East Greenland (Milne Land Formation) during continental breakup and opening of the North Atlantic Ocean. This microanalytical study highlights the ability to conduct rapid Pb isotopic measurements in low-Pb concentration materials (e.g., <2 ppm Pb in plagioclase) at high spatial resolution by LA-ICP-MS with precision sufficient to constrain a range of magmatic processes in layered intrusions and other feldspar-bearing rocks preserved in the geological record.