This dataset presents chemical crosslinking mass spectrometry (CL-MS) analysis of protein-protein interactions between HIV-2 Vpx and PHD3. The experimental data includes MS spectra obtained from protein complexes comprising recombinant Vpx and PHD3 crosslinked using DSBU under physiological conditions. The samples underwent tryptic digestion following standard proteomics protocols, and the resulting peptides were analyzed using high-resolution LC-MS/MS.