Experiments that use direct C-13 detection and take advantage of the slower relaxation of C-13 magnetization compared to H-1 offer an attractive strategy for extending the limits of NMR to include larger, highly dynamic, or paramagnetic proteins. Because carbonyl carbons (C-13') suffer from serious relaxation enhancement as a consequence of their large chemical shift anisotropy, deuterated a carbons are the preferred nuclei for C-13 detection in large and/or fast relaxing systems. However, direct detection of C-13 alpha is not straightforward owing to the presence of one-bond C-13-C-13 couplings with 13C' and C-13 beta that split the signals into multiples and hence reduce the sensitivity. Here we present the use of C-13 enrichment at alternating carbon sites and deuteration the C alpha position to overcome these difficulties. The desired labeling pattern is achieved by expressing the protein in E.coli in D2O with either [2-C-13] or [1,3-C-13] glycerol as the carbon source. With this labeling strategy, we show that complete assignment of the main chain (including prolyl residues) can be achieved with a single CaN HSQC experiment. This approach offers advantages for the detection of NMR signals from sites with fast nuclear relaxation and offers promise for investigations of larger proteins and/or protein complexes that are inaccessible by proton-detected experiments.