We report observations from the Hubble Space Telescope (HST) of Cepheid variables in the host galaxies of 42 Type Ia supernovae (SNe Ia) used to calibrate the Hubble constant (
H0). These include the complete sample of all suitable SNe Ia discovered in the last four decades at redshift z0.01, collected and calibrated from 1000 HST orbits, more than doubling the sample whose size limits the precision of the direct determination of H0. The Cepheids are calibrated geometrically from Gaia EDR3 parallaxes, masers in NGC 4258 (here tripling that sample of Cepheids), and detached eclipsing binaries in the Large Magellanic Cloud. All Cepheids in these anchors and SN Ia hosts were measured with the same instrument (WFC3) and filters ( F555W, F814W, F160W) to negate zero-point errors. We present multiple verifications of Cepheid photometry and six tests of background determinations that show Cepheid measurements are accurate in the presence of crowded backgrounds. The SNe Ia in these hosts calibrate the magnituderedshift relation from the revised Pantheon+ compilation, accounting here for covariance between all SN data and with host properties and SN surveys matched throughout to negate systematics. We decrease the uncertainty in the local determination of H0 to 1 km s1 Mpc1 including systematics. We present results for a comprehensive set of nearly 70 analysis variants to explore the sensitivity of H0 to selections of anchors, SN surveys, redshift ranges, the treatment of Cepheid dust, metallicity, form of the periodluminosity relation, SN color, peculiar-velocity corrections, sample bifurcations, and simultaneous measurement of the expansion history. Our baseline result from the CepheidSN Ia sample is H0 = 73.04 1.04 km s1 Mpc1, which includes systematic uncertainties and lies near the median of all analysis variants. We demonstrate consistency with measures from HST of the TRGB between SN Ia hosts and NGC 4258, and include them simultaneously to yield 72.53 0.99 km s1 Mpc1. The inclusion of high-redshift SNe Ia yields H0 = 73.30 1.04 km s1 Mpc1 and q0 = 0.51 0.024. We find a 5 difference with the prediction of H0 from Planck cosmic microwave background observations under CDM, with no indication that the discrepancy arises from measurement uncertainties or analysis variations considered to date. The source of this now long-standing discrepancy between direct and cosmological routes to determining H0 remains unknown.