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T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to >= 3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPAR alpha)-dependent and if suppression is associated with specific targeting of T-or B-cells, three separate experiments were conducted: (1) female PPAR alpha constitutive knockout (PPAR alpha KO; B6.129S4-Ppar(tm1Gonz)N12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific IgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected for analyses of antigen-specific IgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to >= 1.88mg PFOA/kg suppressed the TIAR; exposure to 30mg PFOA/kg suppressed the TDAR in both PPAR alpha KO and WT mice. The percentage of splenic B-cells was unchanged. Results obtained in the PPAR alpha KO mice indicated that PPAR alpha suppression of TDAR was independent of PPAR alpha involvement. Suppression of the TIAR and the TDAR with minimal lymphocyte sub-population effects suggested that effects on humoral immunity are likely mediated by disruption of B-cell/plasma cell function.