The first observation of top quark production in proton-nucleus collisions is reported using proton-lead data collected by the CMS experiment at the CERN LHC at a nucleon-nucleon center-of-mass energy of √sNN=8.16 TeV. The measurement is performed using events with exactly one isolated electron or muon candidate and at least four jets. The data sample corresponds to an integrated luminosity of 174 nb−1. The significance of the t¯t signal against the background-only hypothesis is above 5 standard deviations. The measured cross section is σt¯t=45±8 nb, consistent with predictions from perturbative quantum chromodynamics.Received 21 September 2017DOI:https://doi.org/10.1103/PhysRevLett.119.242001Published by the American Physical Society under the terms of the Creative Commons Attribution 4.0 International license. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.© 2017 CERN, for the CMS CollaborationPhysics Subject Headings (PhySH)Research AreasParticle & resonance productionPhoton, lepton & quark productionRelativistic heavy-ion collisionsNuclear Physics