Acid sulfate soils (ASS) are a major problem around the world. Oxidation of these sulfide-rich sediments by anthropogenic disturbance results in production and release of sulfuric acid. Subsequent rise in the water table due to rain may result in sulfuric acid and heavy metal ions leaching out of the sediments into nearby estuaries, leading to their acidification. Anecdotal evidence exists that flood waters containing ASS leachate may cause adult Sydney rock oysters Saccostrea glomerata to become immune-suppressed, leading to higher mortality rates from the paramyxean parasite Marteilia sydneyi (aetiological agent of QX disease). In the current study, adult S. glomerata were exposed to a seawater matrix of varying salinity, sulfuric acid and Al3+ for 48 h, and the expression of 7 genes involved in immunity were measured by quantitative reverse-transcription polymerase chain reaction. A change in salinity from 35 to 15 ppt caused a 1.7-fold down-regulation in the expression of peroxiredoxin 6 gene (p < 0.05). The expression of peroxiredoxin 6 was still down-regulated 5 d after oysters were returned to full-strength seawater (35 ppt). Changes in salinity, sulfuric acid and Al3+ concentration had no effects on the expression of other target genes (p > 0.05). The effects of salinity, sulfuric acid and Al3+ on the ability of immune genes to respond to microbial invasion were also investigated by exposing oysters to the seawater matrix for 40 h, followed by injection with heat-killed Vibrio alginolyticus bacteria. A drop in salinity coupled with V. alginolyticus injection resulted in down-regulation of peroxiredoxin 6 and C1q-like protein (p < 0.05). Apart from C1qlike protein, exposure to sulfuric acid and Al3+ had no significant effects on the response of target genes to stimulation by V. alginolyticus (p > 0.05). These results support that reduced salinity, and not estuary acidification, is the main environmental stressor resulting in S. glomerata becoming immunocompromised during the QX disease risk period.