Trichloroethylene (trichloroethene, TCE) is a widely used organic solvent and a common environmental and occupational contaminant. Apart from diseases like cancer and heart defects, TCE exposure has also been implicated in the development of various autoimmune diseases (ADs), such as systemic lupus erythematosus (SLE), systemic sclerosis and fasciitis, both from occupational and environmental exposures. Experimental studies using MRL+/+ mice as an animal model also support an association between TCE exposure and autoimmunity. Increasing evidence suggests that free radical-mediated reactions could play a potential role in the pathogenesis of ADs, and TCE exposure is known to cause oxidative stress both in vivo and in vitro. Recent studies have contributed to the understanding of the role of oxidatively modified proteins, especially lipid peroxidation-derived aldehyde (LPDA)-modified proteins in TCE-induced autoimmune response. These studies support that oxidative modification of endogenous proteins leads to structural alterations, resulting in the formation of neoantigens which elicit autoimmune responses by stimulating T and/or B lymphocytes, particularly Th1 and Th17 lymphocytes. More detailed studies to understand the distinct pathways by which oxidative stress contributes to autoimmunity, especially mapping of gene expression, analyzing proteome, blocking/inhibiting specific signal transduction pathways will also unravel critical mechanisms in TCE-mediated autoimmunity.