With the increase in global mean surface temperature predicted for the near future, stream water temperature will also increase. Simultaneously, water quality is likely to decrease (e.g., due to increases in nutrient and pollutant concentrations). The objective of this study was to evaluate the individual and combined effects of increases in water temperature and nutrients concentration on periphyton respiration, as a surrogate for stream metabolism. Stones naturally colonized with periphyton in an unpolluted mountain stream in Central Portugal were sampled seasonally over a year, and incubated in the laboratory under two water temperatures (ambient and 4°C elevated) and two nutrients concentration levels (ambient and ∼6× higher inorganic dissolved nitrogen, ∼2× higher soluble reactive phosphorous concentrations). Overall, increases in water temperature stimulated periphyton respiration to a larger extent than did increases in nutrients concentration. In spring, the simultaneous increase in water temperature and nutrients concentration stimulated periphyton respiration beyond expected from the individual effect of each factor. These results indicate that synergistic interactions between factors might occur under certain environmental conditions, suggesting that care should be taken when predicting the combined effect of changes in multiple factors from their individual effects. The observed stimulation of periphyton respiration promoted by increased temperature and nutrients concentration can lead to changes in streams carbon budgets, with a positive feedback for global warming, as more CO2 might be released to the atmosphere.