A computer algorithm that determines the 1HN, 15N, 13C alpha, 1H alpha, 13C beta and 1H beta chemical-shift assignments of protein residues with minimal human intervention is described. The algorithm is implemented as a suite of macros that run under a modified version of the FELIX 1.0 program (Hare Research, Bothell, WA). The input to the algorithm is obtained from six multidimensional, triple-resonance experiments: 3D HNCACB, 3D CBCA(CO)HN, 4D HNCAHA, 4D HN(CO)CAHA, 3D HBHA(CO)NH and 3D HNHA(Gly). For small proteins, the two 4D spectra can be replaced by either the 3D HN(CA)HA, 3D H(CA)NNH, or the 15N-edited TOCSY-HSQC experiments. The algorithm begins by identifying and collecting the intraresidue and sequential resonances of the backbone and 13C beta atoms into groups. These groups are sequentially linked and then assigned to residues by matching the 13C alpha and 13C beta chemical-shift profiles of the linked groups to that of the protein's primary structure. A major strength of the algorithm is its ability to overcome imperfect data, e.g., missing or overlapping peaks. The viability of the procedure is demonstrated with two test cases. In the first, NMR data from the six experiments listed above were used to reassign the backbone resonances of the 93-residue human hnRNP C RNA-binding domain. In the second, a simulated cross-peak list, generated from the published NMR assignments of calmodulin, was used to test the ability of the algorithm to assign the backbone resonances of proteins containing internally homologous segments. Finally, the automated method was used to assign the backbone resonances of apokedarcidin, a previously unassigned, 114-residue protein.