The South Pole Telescope (SPT) is currently surveying 2500 deg^2 of the southern sky to detect massive galaxy clusters out to the epoch of their formation using the Sunyaev-Zel'dovich (SZ) effect. This paper presents a catalog of the 26 most significant SZ cluster detections in the full survey region. The catalog includes 14 clusters which have been previously identified and 12 that are new discoveries. These clusters were identified in fields observed to two differing noise depths: 1500 deg^2 at the final SPT survey depth of 18 μK arcmin at 150 GHz and 1000 deg^2 at a depth of 54 μK arcmin. Clusters were selected on the basis of their SZ signal-to-noise ratio (S/N) in SPT maps, a quantity which has been demonstrated to correlate tightly with cluster mass. The S/N thresholds were chosen to achieve a comparable mass selection across survey fields of both depths. Cluster redshifts were obtained with optical and infrared imaging and spectroscopy from a variety of ground- and space-based facilities. The redshifts range from 0.098 ≤ z ≤ 1.132 with a median of z_(med) = 0.40. The measured SZ S/N and redshifts lead to unbiased mass estimates ranging from 9.8 × 10^(14) M_☉ h^(–1)_(70) ≤ M _(200(ρmean)) ≤ 3.1 × 10^(15) M_☉ h^(–1)_(70). Based on the SZ mass estimates, we find that none of the clusters are individually in significant tension with the ΛCDM cosmological model. We also test for evidence of non-Gaussianity based on the cluster sample and find the data show no preference for non-Gaussian perturbations.