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High-frequency transmission lines crosstalk reduction using spacing rules is treated in this paper. Two of the most popular planar transmission line configurations, namely microstrip and stripline, commonly used in printed circuit boards and radio frequency/microwave integrated circuits, are considered in this work. The trace separation between two adjacent transmission lines of each type is stepwise increased as function of the trace width. The single-ended transmission line structures are numerically investigated by a frequency-based 3-D full-wave electromagnetic analysis tool. A particular case using coated microstrip transmission lines has been fabricated, along with some calibration structures, to allow direct measurement and experimental analysis of crosstalk between the single-ended transmission lines. The test structures are characterized at high-frequency (up to 20 GHz) with scattering parameters using a vector network analyzer. The experimental results are compared with the simulation data, and some conclusions and suggestions on the impact and use of spacing rules for high-frequency crosstalk reduction between single-ended transmission lines are presented. These investigations emphasize the necessity of reevaluating classical design rules for their suitability in high-frequency applications.