Little is known of the role of specific environmental factors in promoting autoimmune disorders such as systemic lupus erythematosus (SLE). This study addresses how exposure to phthalates, common environmental factors in foods, and biomedical devices could affect the immune functions of resistant and autoimmune-prone mice. We have previously shown that immunization with ortho-phthalate evokes anti-DNA antibody in BALB/c and NZB/W F1 mice, but only the latter suffer from nephritis and high mortality. BALB/c mice, in contrast, develop idiotype-specific CD8+ suppressor T cells downregulating autoreactive B cells. Here we report that all phthalate-isomers (ortho-, meta- and para-) are capable of inducing anti-DNA antibody responses and SLE-like syndromes. Kidney pathology worsens in NZB/W F1 and to a degree, in C57BL/6 mice after repeated exposure to phthalates. Only BALB/c and DBA/2 overcome adverse autoreactivity by induction of Ts cells; but in vivo depletion of these T cells renders these strains susceptible to autoreactivity. Anti-DNA antibodies in affected NZB/W F1 are largely IgG2a-type, while in BALB/c, DBA/2, and C57BL/6 mice IgG1-type. This is further corroborated by cytokine analyses that imply corresponding Th1/Th2 involvement. In summary, the commonly used phthalates appear harmful to susceptible strains, while BALB/c and DBA/2 are spared due to induction of Ts cells.