In contrast to mammals, the blood from other vertebrates such as fish contains nucleated red cells. Using a fathead minnow ( Pimephales promelas) oligonucleotide microarray, we compared altered transcripts in the liver and whole blood after exposure to environmentally relevant concentrations of perfluorooctanesulfonic acid (PFOS) and a mixture of seven types of perfluoro alkyl substances (PFAS), including perfluorooctanoic acid (PFOA). We used quantitative polymerase chain reactions and cell-based assays to confirm the main effects and found that blood responded with a greater number of altered genes than the liver. The exposure to PFAS altered similar genes with central roles in a cellular pathway in both tissues, including estrogen receptor α and peroxisome proliferator activator β and γ, indicating that the genes previously associated with PFAS exposure are differentially expressed in blood and liver. The altered transcripts are involved with cholesterol metabolism and mitochondrial function. Our data confirmed that PFAS are weak xenoestrogens and exert effects on DNA integrity. Gene expression profiling from blood samples not related with the immune system, including very-low-density lipoprotein, vitellogenin, estrogen receptor, and thyroid hormone receptor, demonstrated that blood is a useful tissue for assessing endocrine disruption in non-mammalian vertebrates. We conclude that the use of blood for non-lethal sampling in genomics studies is informative and particularly useful for assessing the effects of pollution in endangered species. Further, using blood will reduce animal use and widen the experimental design options for studying the effects of contaminant exposure on wildlife.