Rivers are impacted by multiple stressors that affect their ecological and chemical quality, water availability and ecosystem functions. Stressors can interact to create synergistic, additive or antagonistic effects, but experimental studies on fish encompassing more than one stressor are seldom found. Thus there is the need to study stressors through multifactorial approaches that analyse the impact of fish exposure to multiple stressors, stressor interactions, and evaluate fish sensitivity to stress combinations. Some of the most common impacts to Mediterranean rivers are of two natures: i) hydromorphological and ii) diffuse pollution. Therefore, the present study aims at studying the responses of potamodromous fish facing combinations of: 1) a primary stressor (three levels of water scarcity and connectivity reduction – naturally occurring in Mediterranean systems), and 2) a secondary stressor (three levels of oxygen decrease due to organic load – of anthropogenic nature). For that, schools of five wild fish from a potamodromous species (Luciobarbus bocagei) were placed in a flume equipped with see-trough sidewalls, to allow for behavioural analysis, and subjected to different combinations of the stressors. The results of this work, and the observed correlations between behaviour and stressor combination, improve our understanding of the effects of the interaction of natural and man-induced stressors on potamodromous fish species, making possible to implement effective management and restoration policies. This work progresses from single variable manipulative experiments to multifactorial experiments, allowing a dose-response surface to be determined in order to assist prediction of fish responses upon actual or projected pressure scenarios.