Herein, we report a systematic investigation of the effects of meso-substituents on dithiadioxaisophlorins (S2O2Iphs, 1; Figure ), which are attainable stable isophlorin derivatives with strong antiaromatic characteristics. While pentafluorophenyl-substituted S2O2Iph (1a) was reported by Anand and coworkers, we synthesized two new derivatives with 3,5-bis(trifluoromethyl)phenyl (1b) and 5-cyanothien-2-yl (1c) substituents. Combining experimental techniques and computational methods, we investigated how different meso-substituents influence the electronic properties of these compounds, focusing on the interplay between steric demands and electronic effects in controlling antiaromaticity.