Orange-spotted grouper Epinephelus coioides reared at 34‰ and 27 °C were abruptly transferred to 6‰, 20‰ and 34‰ (control) and examined for innate cellular and humoral parameters after 3–96 h. Total leucocyte count (TLC), respiratory burst (RB), phagocytic activity (PA), alternative complement pathway (ACP) and lysozyme activity were significantly decreased 3–6 h, 3–6 h, 3–96 h, 3–96 h and 3–96 h, respectively after transferal into 6‰ salinity. TLC, RB and PA significantly increased after 3–48 h, 3–96 h and 3–24 h, respectively, with recovery of TLC and PA after 96 h and 48–96 h, whereas ACP and lysozyme activity significantly decreased 3–96 h after being transferred to 20‰. In another experiment, grouper reared at 34‰ and 27 °C were injected with Vibrio alginolyticus grown in tryptic soy broth (TSB) at 2.3 × 109 colony-forming units (cfu) fish−1 and then transferred to 6‰, 20‰ and 34‰ (control). The cumulative mortalities of V. alginolyticus-injected fish held in 6‰ were significantly higher than in injected fish held at 20‰ and 34‰. It was concluded that grouper E. coioides encountering a 34‰–6‰ salinity drop stress exhibited a depression in immunity as evidenced by decreased cellular and humoral parameters and increased susceptibility to V. alginolyticus. Grouper encountering a salinity stress drop from 34‰ to 20‰, however, exhibited decreased humoral immune parameters but also increased TLC and cellular immune parameters, indicating immunomodulation.