We evaluated the potential interaction of pesticide effect and predatory fish on behavior and mortality of a stream mayfly. Experiments in laboratory stream microcosms compared the activity, drift, and mortality of Baetis mayfly nymphs in the absence of fish with that in the presence of Cape galaxias (Galaxias zebratus), both species inhabiting the same stream environments in the Western Cape of South Africa. These two predator treatments were combined with exposure either to no pesticide or to 0.2 μg/L of the organophosphate insecticide azinphos-methyl (AZP) or 0.2 μg/L of the pyrethroid insecticide fenvalerate (FV). Such pesticide levels are known from transient spraydrift- or runoff-related pesticide input into running waters. Each of the six combinations was replicated six times as 30-min trials during the day and effects were analyzed using 2 × 2 factorial analysis of variance (ANOVA). A single exposure to either fish or pesticide significantly increased the absolute activity of mayflies, measured as number of animals visible on top of stones, and the absolute mayfly drift in the fish treatment and in the FV treatment but did not increase the mortality above 0.8%. The combination of predator presence and sublethal pesticide exposure resulted in a significant increase in the mortality rate, to about 9% in the AZP × fish and 25% in the FV × fish treatment, although the activity and drift rates were not increased compared with the single-stressor treatments. Two-by-two factorial ANOVA and the comparison of expected and measured responses indicated that the mortality resulted from a synergistic interaction of the two stressors. The observed mortality was without exception caused by predation of the fish on drifting mayflies. The relative drift rate in the FV × fish treatment was decreased, again due to a synergistic interaction, which suggests an active drift avoidance reaction of the mayflies exposed to the combined pesticide × fish treatment, in contrast with those exposed just to FV. We conclude that the drift response of mayflies to transient sublethal pesticide exposure results in a synergistically increased adverse effect in the presence of predatory fish.