The structure of the 60 kDa E. coli sulfite reductase hemoprotein (SiRHP) was determined by using multiwavelength anomalous diffraction (MAD) to exploit the relatively small anomalous signals produced near the Fe K absorption edge from the protein's native Fe(4)S(4) cluster and siroheme Fe atom. Because of systematic measurement error, generation of useful MAD data required rejection of outlying intensity observations that were only identified by careful manual scrutiny of the observed intensities and single parameter scaling among wedges of diffraction data. The key steps for obtaining effective phases were local anisotropic scaling between Bijvoet pairs and among wavelengths, extraction of phase information from unmerged observations, and refinement of the anomalous scattering model. Important factors for positioning the anomalous scattering model included removal of aberrant coefficients from Patterson syntheses, positional refinement of the Fe positions against MAD-derived normal-scattering amplitudes, and systematic searches of cluster orientation that attempted to optimize agreement between observed and calculated MAD intensities. To obtain MAD phases for reflections that were underdetermined for least-squares methods, parameters necessary for defining phase-probability distributions had to be estimated from the anomalous scattering model. The MAD phase distributions, when combined probabilistically with otherwise insufficient MIR phase information, led to the determination of the SiRHP structure. The techniques developed and lessons learned from the SiRHP MAD experiment should be applicable to the design of MAD experiments on other macromolecules.