Abstract: Nitrite or sulfide accumulation has always been a challenge for the treatment of saline or hypersaline wastewater. Simultaneous sulfide and nitrite removal process (SSNIR) targeting sulfide and nitrite as substrates, is a robust and potentially practical autotrophic denitrification biotechnology. Its feasibility to operate under hypersaline wastewater is not fully understood so far. Therefore, the current work explored the practicability of SSNIR to treat saline or hypersaline wastewater, evaluation of the toxicological effects of substrate and salinity on the denitrification and sulfide removal performance and product types. Additionally, the type of combined toxicity of substrate and salinity to SSNIR was determined. The results showed that the respective IC50 values for substrate shock on Specific sulfide oxidation activity (SSOA) and Specific denitrification activity (SDA) were 289.29 mg S/L and 300.92 mg S/L. The IC50 values of salinity shock on SSOA and SDA were 6.19 % wt (98.07 ms/cm) and 3.78 % wt (61.74 ms/cm), even the salinity level as high as 13.2 % wt (204 ms/cm) resulted in the reduction of 40 % nitrite removal efficiency. At salinity value>2.4 % wt (41 ms/cm), increase in salinity casted significantly positive effect on the nitrous oxide emission (P < 0.01). In addition, the combined salinity, substrate toxicity and salinity exposure value of<2.67 % wt (45 ms/cm) on SSNIR showed synergistic inhibition. A further increase in salinity (>45 ms/cm) alleviated the strength of synergistic inhibition and the effect on SSOA was identified as antagonistic inhibition.