Schistosomiasis is only second to malaria in terms of public health importance among parasitic diseases. Hence morbidity and mortality associated with Schistosoma mansoni are mainly the result of periportal fibrosis of the liver. With the objective of evaluating the association of total serum antioxidants and intensity of S. mansoni infection a cross sectional study was conducted from February 2011 to June 2011 involving 414 individuals and 30 controls from S. mansoni non-endemic area. The study groups were selected using systematic random sampling technique and data were collected using a pre-tested clinical questionnaire, ulthersonographic examinations of the liver and serum ferric reducing antioxidant power (FRAP) assays. Prevalence of Schistosoma mansoni infection and periportal fibrosis in Cheretee was 36.72% and 9.42%, respectively. Prevalence of periportal fibrosis and intensity of infection had a sharp rise in the age group 11-20 years, reached its peak in the 21 to 30-year age group, and started to decline thereafter up to >40. Age, sex and intensity of infection were strongly associated with periportal fibrosis development (p<0.05). Mean total serum antioxidant concentrations were significantly lower in study subjects who were from S. mansoni endemic area (96.5 μM/L) compared with healthy participants from Addis Ababa (339.9 μM/L). However, mean total serum antioxidant concentration were not significantly different among PPF positive and negative individuals from S. mansoni endemic area. Finally, further studies are recommended on the cause of this low antioxidant concentration.