In order to investigate the association between effects of genetic polymorphisms of GSTT1 and GSTM1 and depression score of individuals chronically exposed to natural sour gas containing sulfur compounds, the present cross-sectional study was done. The study was performed on 124 healthy females living in the polluted area of Masjid-i-Sulaiman (MIS; Khozestan province, southwest of Iran). The GSTT1 and GSTM1 genotypes were determined using a polymerase chain reaction (PCR)-based method. Depression and hopelessness scores were determined by means of Beck's depression inventory (BDI) and Beck's hopelessness scale (BHS), respectively. The BHS score was positively correlated to the depression score (beta=0.687, t=10.474, p<0.001). The GSTT1 active genotype decreased the BDI score (beta=-0.161, t=-2.451, p=0.016). Polymorphism of GSTM1 may not be a good predictive factor for BDI (beta=-0.056, t=-0.857, p=0.393). There is no evidence for additive effect of GSTM1 and GSTT1 polymorphisms on BDI score. It is supposed that chronic exposure to natural sour gas may positively associated with DNA strand breaks and apoptosis in brain, especially in GSTT1 null genotype persons; finally living in the contaminated areas of MIS is associated with high BDI score.