Differential signaling is very common for high frequency integrated circuit design. Accurate multimode de-embedding at multigigahertz frequencies, however, is a major challenge. The differential and common-mode parameters can be obtained by converting the measured four-port nodal S-parameters into the mixed-mode form. Under certain conditions, it is possible to separate the modes and consider only the entries corresponding to the differential S-parameters. This allows to reduce the measured 4 × 4 matrix to a 2 × 2 matrix and consider the differential device as a two-port network. Thus, the standard de-embedding techniques, derived for two-port networks, can be applied to differential S-parameters. The purpose of this paper is to investigate the applicability of this approach for on-wafer measurements. We describe analytically the conditions under which this method is valid. As an example, a 2:1 transformer, manufactured in Infineon's 0.13 μm CMOS (complementary metal-oxide semiconductor) process, has been characterized. On-chip de-embedding structures have been fabricated using the same process. The results obtained using Short-Open, Thru-Line, and Thru-Line-Reflect de-embedding techniques are compared. Additionally, the results are verified by simulation of a device under test having high-mode conversion.