Abstract Stressful experiences can modulate multiple sclerosis, but stress protection is currently not considered a treatment option. Here, we show that maternal deprivation, an adverse stress experience in infancy, increases emotionality in behavioral tests of adult female Lewis rats and concomitantly causes a more severe course of experimental autoimmune encephalomyelitis. Treatment of these effects in adulthood by chronic antidepressants (imipramine) reversed the behavioral symptoms and attenuated the course of the encephalomyelitis in deprived rats. Increased IL-4 plasma levels accompanied the protective-like effects of antidepressants. In contrast, attempts to prevent these effects in infancy by tactile stimulation aggravated the encephalomyelitis, possibly by decreasing corticosterone and increasing IFN-γ levels during the disease. This indicates that antidepressants exert protective effects in an animal model of multiple sclerosis, and suggests that drugs modifying stress responsiveness may have a potential role as adjuvant treatment of the disease.