This study evaluated how Synechocystis sp. PCC 6803 responds to high total dissolved solids (TDS) associated with eliminating nutrient limitation during long-term operation of a photobioreactor. The unique feature is that the TDS were not dominated by Na+ and Cl-, as in seawater, but by HCO3- and NO3- from nutrient delivery. The TDS-stress threshold was about 10 g/L: Whereas inorganic N and P limitations slowed the rate of inorganic C (CO uptake in the light, TDS stress was manifested most strongly as a substantial increase of endogenous respiration rate at night. Relief from TDS stress was incomplete when lowered pH led to a HCO3- increase (560 mg C/L as a threshold). Impaired photosynthesis led to a cascade of reduced C-i-uptake, pH decrease, HCO3- accumulation, and HCO3--associated stress. Thus, long-term photobioreactor operation requires balancing the delivery rates of CO2, N, P, and other TDS components to avoid general and C-i-associated TDS stresses. (C) 2012 Elsevier Ltd. All rights reserved.