An exact full matrix analysis of 2D NOESY spectroscopy has been extended to 3D homonuclear NOE-NOE spectroscopy and applied to the simulation of NOE-NOE spectra of the Dickerson dodecamer d(CGCGAATTCGCG)2 and a tandem GA mismatched decamer deoxynucleotide duplex d(CCAAGATTGG)2. The exact method has been compared with the approximation method based on Taylor expansions. It has been found that the approximations using one or two terms in the Taylor expansion series are generally inadequate for simulations of 3D NOE-NOE volumes and fail at very short mixing times, depending on the motional properties of the biomolecule in question. Specifically, the first-order approximation fails at tau c tau m > or = 1.8 x 10(-10) s2 for both the dodecamer and the decamer if an RMS error in the volumes of < 50% is desired.