Assessment of the reliability of microarray experiments as well as their cross-laboratory/platform reproducibility rise as the major need. A critical challenge concerns the design of optimal Universal Reference RNA (URR) samples in order to maximize detectable spots in two-color/channel microarray experiments, decrease the variability of microarray data, and finally ease the comparison between heterogeneous microarray datasets. Towards this target we devised and present an in-silico (binary) optimization process the solutions of which present optimal URR sample designs. Setting a cut-off threshold value over which a gene is considered as detectably expressed enables the process. Experimental results are quite encouraging and the related discussion highlights the suitability and flexibility of the approach.