In many large European rivers, the number of typical riverine insect species, such as mayflies, stoneflies, and caddisflies, is greatly reduced compared to historic records. This can no longer be explained by high concentrations of a relatively small number of dominant toxicants since many rivers have changed from heavily contaminated systems with a few selected key toxicants to systems with a complex contamination. This contamination consists of many substances in low concentrations coinciding with other unfavorable conditions, such as low oxygen concentrations. It was hypothesized that the joint adverse effects of such multiple stressors may be a steering factor in the distribution of riverine insect species. The aim of this study was therefore to determine the combined effects of toxicants and oxygen depletion. To this purpose, larvae of the indigenous riverine mayfly Ephoron virgo were exposed to two different model toxicants, copper and diazinon, under normoxia and hypoxia (50% air saturation) conditions. The median effective concentrations for mortality for copper were significantly lower in the hypoxia treatments than in the normoxia treatments. For diazinon, no differences were observed between two treatments differing in dissolved oxygen levels, and therefore we argue that interactions between multiple stressors may be compound specific. It is concluded that the combination of toxicants and lowered oxygen may have a stronger impact than can be expected based on the adverse effects of the individual factors and that standard toxicity tests may be insufficient alone to determine the impact of human activities on the ecological state of riverine communities. Instead, attention needs to be paid to more environmentally realistic nonoptimal conditions in toxicity testing to adequately fulfill the needs of ecological recovery programs.