Organic electrochemical devices and their operational stability depend on the reversible switching between the neutral and doped states of redox-active materials. The charged, radical state of doped π-conjugated molecules can be reactive toward radical and/or ionic side reactions that degrade the functionality of the material and device. In this work, we focus on a group of thiophene-based conjugated molecules and investigate how substituents, commonly used to modulate optical and redox properties, can influence radical cationic stability. Subtle changes in the number and position of electron-donating substituents on the conjugated moiety were shown to affect the localization of the unpaired electron in the radical cation, leading to distinct degradation pathways. Using a combination of electrochemistry, mass spectrometry, UV−visible spectroscopy, single-crystal Xray diffraction analysis, and theoretical calculations, we identify degradation pathways involving either demethylation or σdimerization coupled with end-group loss, and correlate to the electronic structure of the radical cation. We explore the chemistry and conditions favoring these degradation events and provide new insights into understanding and improving the stability of redoxactive conjugated systems.