To explore the possibility that the active center of the di-iron hydrogenases, the [FeFe](H) subcluster. can serve by itself as an efficient hydrogen-producing catalyst, we perform comprehensive calculations of the catalytic properties of the subcluster in vacuo using first principles density functional theory. For completeness, we examine all nine possible geometrical isomers of the Fe(II)Fe(I) active-ready state and report in detail on the relevant ones that lead to the production of H-2. These calculations, carried out at the generalized gradient approximation level, indicate that the most efficient catalytic site in the isolated [FeFe](H) subcluster is the Fe-d center distal (d) to the [4Fe-4S](H) cluster, the other iron center site, the proximal Fe-p, also considered in this study, has much higher energy barriers. The pathways with the most favorable kinetics (lowest energy barrier to reaction) proceed along configurations with a CO ligand in a bridging position. The most favorable of these CO-bridging pathways start from isomers where the distal CN- ligand is in up position, the vacancy V in down position, and the remaining distal CO is either cis or trails with respect to the proximal CO. These isomers. not observed in the available enzyme X-ray structures, are only marginally less stable than the most stable nonbridging F-ed-CO-terminal isomer. Our calculations indicate that this CO-bridging CN-up isomer has a small barrier to production of H, that is compatible with the observed rate for the enzyme. These results suggest that catalysis of H-2 production could proceed on this stereochemically modified [FeFe]H subcluster alone, thus offering a promising target for functional bioinspired catalyst design.