The fluctuations of mercury levels (Hg) in fish consumed by sport fishers in North-Eastern America depend upon a plethora of interrelated biological and abiological factors. To identify the dominant factors ultimately controlling fish Hg concentrations, we compiled mercury levels (Hg) during the 1976-2010 period in 90 large natural lakes in Quebec (Canada) for two major game species: northern pike (Esox lucius) and walleye (Sander vitreus). Our statistical analysis included 28 geographic information system variables and 15 climatic variables, including sulfate deposition. Higher winter temperatures explained 36% of the variability in higher walleye growth rates, in turn accounting for 54% of the variability in lower Hg concentrations. For northern pike, the dominance of a flat topography in the watershed explained 31% of the variability in lower Hg concentrations. Higher mean annual temperatures explained 27% of the variability in higher pike Hg concentrations. Pelagic versus littoral preferred habitats for walleye and pike respectively could explain the contrasted effect of temperature between the two species. Heavy logging could only explain 2% of the increase in walleye Hg concentrations. The influence of mining on fish Hg concentrations appeared to be masked by climatic effects.