Real crystals are composed of a mosaic of domains whose misalignment is evaluated by their level of “mosaicity” using X-ray diffraction. In thermo-induced spin-crossover compounds, the crystal may be seen as a mixture of metal centres, some being in the high-spin (HS) state and others in the low spin (LS) state. Since the volume of HS and LS crystal packings are known to be very different, the assembly of domains within the crystal, i.e., its mosaicity, may be modified at the spin crossover. With little data available in the literature we propose an investigation into the temperature dependence of mosaicity in certain spin-crossover crystals. The study was preceded by the examination of instrumental factors, in order to establish a protocol for the measurement of mosaicity. The results show that crystal mosaicity appears to be strongly modified by thermal spin-crossover; however, the nature of the changes are probably sample dependent and driven, or masked, in most cases by the characteristics of the crystal (disorder, morphology …). No general relationship could be established between mosaicity and crystal properties. If, however, mosaicity studies in spin-crossover crystals are conducted and interpreted with great care, they could help to elucidate crucial crystal characteristics such as mechanical fatigability, and more generally to investigate systems where phase transition is associated with large volume changes.