We demonstrated that the toxicity of the harmful bloom dinoflagellate Karlodinium veneficum is regulated by both CO 2 concentrations and phosphate availability. Semi-continuous cultures were grown in a factorial experiment under all combinations of 3 CO 2 levels (230, 430 and 745 ppm) and 2 phosphate conditions (0.5 and 20 µM). After steady-state acclimation was achieved, karlotoxin cellular quotas and growth rates were determined in all 6 treatments. This strain produced both types of karlotoxin, KmTx-1 and KmTx-2. Chlorophyll a-normalized production of the 2 types of karlotoxins was much higher in P-limited cultures compared with P-replete ones under the same CO 2 conditions. Increasing CO 2 strongly stimulated production of KmTx-1 and decreased production of KmTx-2 in both treatments, but especially in P-limited cultures. Because the KmTx-1 toxin is an order of magnitude more potent than KmTx-2, total cellular toxicity was increased dramatically at high pCO 2 , particularly in P-limited cultures. Specific growth rates were accelerated by enriched CO 2 in P-replete cultures, but not in P-limited treatments. Growth rates or toxicity of K. veneficum could increase substantially in the future with high CO 2 levels in the ocean, depending on P availability, and so interactions between rising CO 2 and eutrophication could cause major shifts in present day patterns of harmful algal toxin production. These results suggest that over the coming decades, rising CO 2 could substantially increase karlotoxin damage to food webs in the often P-limited estuaries where Karlodinium blooms occur.