Most studies that infer geographic distributions of fish using otolith microchemistry assume that environmental factors (e.g. temperature, salinity) outweigh intrinsic effects (e.g. size, condition); however, this assumption has not been rigorously tested, particularly in marine fish. Here, we report the results of a long-term experimental study of European plaice Pleuronectes platessa L. and explore relationships between blood plasma and ambient water chemistry over a 12 mo reproductive cycle. Overall, blood plasma was found to be highly regulated, with few elements exhibiting strong, if any, correlation with ambient concentrations. This sets a first order limit on the sensitivity of otolith chemistry to fluctuations in ambient seawater chemistry. The observed temporal, ontogenetic and sex-specific variations in blood plasma elemental concentrations indicated significant physiological influences on elemental uptake and processing mechanisms. Physiological variables exerted relatively strong influences on the uptake and regulation of the softer, more thiophilic elements (Mn, Cu, Zn, Se and Pb), as well as Sr and Ca. By contrast, seasonal and sex-related variations were relatively minor among the hard acid metal ions (Li+, Mg2+, K+, Rb+, Ba2+). Overall, plasma elemental concentrations covaried most strongly and consistently with plasma protein concentrations. For this exclusively marine species, seasonal changes in physiology governed intra-annual variations in blood chemistry and, by implication, also regulate ion availability to the otolith. Based on these observations, we recommend that sex and age should be controlled for in future experimental designs using otolith microchemistry to infer stock structure or migration patterns.