Pesticide concentrations are correlated with regional declines in stream invertebrate diversity. However, pesticide effects on stream invertebrate assemblages are complicated by interactions with other stressors and natural environmental gradients. We experimentally examined multiple-stressor effects on stream invertebrate structure and leaf-litter breakdown. We used 24 independent 1000L re-circulating outdoor mesocosms in a semi-orthogonal design. Two pulses of the pesticide malathion were delivered at low and high concentrations (Pulse 1: low at 0.1 and high at 1µgL-1; Pulse 2: at 2.5 and 25 µgL-1), crossed with nitrogen, phosphorus and sediment additions as a single treatment. Malathion degradation was rapid in all treatments likely because of photolysis, hydrolysis influenced by pH, biofilms and sorptive processes (<24hr half-life). There were considerable differences between treatments, where malathion contributed to 48.6% and 87.3% of invertebrate assemblage deviance during Pulse 1 and 2 respectively. Malathion had strong negative effects during Pulse 2, decreasing Ephemeroptera, Plecoptera and Trichoptera abundance (P<0.05), invertebrate richness (P<0.01) and total invertebrate abundance (P<0.01). Despite the dominant effects of malathion, co-occurring agricultural stressors inhibited rates of leaf litter breakdown (P<0.05), stimulated invertebrate densities and weakly mitigated malathion toxicity in mesocosms (PERMANOVA, P≈0.1). Experimental toxicity assays of select sensitive taxa and chemical analysis identified sediment ameliorated malathion effects through alkaline hydrolysis and sorption. Sensitivity-dependent effects were observed where both direct and interactions among stressors were dependent on taxonomic sensitivities. Pesticide effects are difficult to quantify given difficulties in capturing peak exposure, rapid breakdown and pesticide-environment interactions. Among co-occurring stressors however, environmentally relevant pesticide concentrations can have dominant deleterious consequences on ecosystems, causing rapid community shifts and homogenising biota.