Recent research papers published results indicating that Fluoride (F-) exposure can be relate to Oxidative Stress (OS) in humans and animals (Varol E, et al., 2011; Basha and Madhusudhan 2010). Recent animal studies show, that OS induced by F- exposure in vulnerable periods like pregnancies, is associated with damage of offspring affecting especially the normal development of the Central Nervous System (CNS) (Narayanaswamy M, et al., 2010; Basha P, et al., 2011). The aim of this study is to evaluate OS disorder to F- exposure during the pregnancy in humans. A follow-up study was conducted during 2013 and 2014 in two states of Mexico with a history of water contamination with F-. Pregnant women were evaluated in a three monthly period over their whole pregnancies. F- in water (FW) was quantified with an ion selective electrode. The Oxidative Stress Index (OSI) was determined in serum samples by spectrophotometry with the Kit “Rel Assay Diagnostics”. In order to eliminate external factors during all pregnancies, an initial questionnaire and follow-up questionnaires were applied. The FW levels were categorized in two groups according to national and international norms (<1.5 mg/L and > 1.5mg/L). Statistical analysis was carried out using the software SPSS 19. 102 pregnant women were evaluated in the first trimester, 59 and 23 pregnant women continued in the study respectively in the second and third trimester. The levels of OSI in each trimester per group were 4 ± 2 vs 3 ± 2; 3 ± 2 vs 3 ± 2 and 3 ± 1 vs 4 ± 2 respectively. Non-statistical difference was observed between groups (p=0.25, p=0.32 and p=0.9), nevertheless the percentage of abnormal levels were higher in the group of pregnant women with F- exposure >1.5 mg/L in each trimester (69.4 vs 56.2, 93.7 vs 80 and 75 vs 0). This study is the first approach to demonstrate the action mechanism of F- toxicity during human pregnancy.