Fish can be exposed to multiple stressors at the same time, including natural toxins, environmental pollutants or feed contamination. In this study, we report on the effects of controlled exposure of rainbow trout (Oncorhynchus mykiss) to multiple stressors. In doing so, we test the hypothesis that cyanobacterial biomass and arsenic in feed combine to enhance negative effects on fish, including modulation of antioxidant response. The trout (mean weight 288 ± 59 g) were divided into six experimental groups of 25 fish each (C - control group; B - 3% lyophilised toxic cyanobacterial biomass; As5 - arsenic at 5 mg·kg^–1; As50 - arsenic at 50 mg·kg^–1; and two combinations of cyanobacterial biomass and arsenic (B+As5 and B+As50). All indicators of oxidative stress were determined using standard methods, showing significant changes. Overall antioxidant capacity (ferric reducing antioxidant power) decreased significantly in the liver, gills and heart after 10-days, while lipid peroxidation (thiobarbituric acid reactive substances) increased in the liver of groups exposed to cyanobacterial biomass, and in the heart of groups exposed to increased concentrations of arsenic and those under combined exposure. Levels of glutathione reductase showed a significant reduction following exposure, especially in the gills and liver. Our results indicate that the antioxidant system plays an important role in the protective response of tissues to stressors, and especially arsenic.