This study was conducted to assess the compatibility of white shrimp Litopenaeus vannamei and giant freshwater prawn Macrobrachium rosenbergii in the polyculture system. Twelve 0.6 ha intertidal mudflat ponds of shrimp in the region around Hangzhou Bay, China, were divided into four culture systems based on the stocking densities of prawns. The groups were divided into the following: control (CON, no prawn), low stocking density (LSD, 75,000 ha−1), middle stocking density (MSD, 150,000 ha−1) and high stocking density (HSD, 225,000 ha−1) groups. Results showed that the survival (%), final weight, final length and condition factor of reared shrimp exhibited no significant difference among different culture systems. The profits of the polyculture systems significantly increased with prawn stocking density. The mean values of water quality parameters showed no significant difference (p > 0.05) between treatments. Phytoplankton abundance and biomass were significantly reduced in the polyculture groups. Desulforegula (9.39%), Citreicella (4.23%), Gemmobacter (3.66%) and Phycisphaera (2.93%) were the prevailing genera in the CON group. Aeromonas was the most abundant genus in the HSD group. However, most pathogenic bacteria in the pond water were undetected or observed at extremely low levels. The levels of Aeromonas and Pseudomonas sharply increased in the HSD group. These findings suggest that polyculture systems can increase profit without influencing water quality. However, high polyculture at 225,000 ind ha−1 may potentially cause pathogenic bacterial infection. Thus, the recommended model for this polyculture system is shrimp (900,000 ha−1) + prawn (150,000 ha−1).