Fish mercury concentrations result in fish consumption advisories. However, selenium : mercury molar ratios >1 are protective to wildlife and humans. Therefore, we sampled total selenium (TSe) and total mercury (THg) concentrations and molar ratios in sport fish from 50 Idaho (ID) lakes >20 ha and 67 northeastern USA (NE) lakes >1 ha. Sample lakes were selected at random, to obtain unbiased estimates of mean fish tissue levels, with known confidence limits, for target populations of 95 ID lakes >20 ha in surface area and 12,557 NE lakes >1 ha. Bass and salmonids presented the greatest potential mercury toxicity risk to consumers based on their higher mercury content, desirability as game fish, and widespread distributions. Fish tissue THg exceeded safe consumption criteria in an estimated 20–80% of the lakes in the two regions and TSe exceeded safe consumption thresholds in an estimated 0–20% of the lakes in the two regions. However, the Se : Hg molar ratio was >1 in an estimated 90–97% of fish tested from NE and ID lakes. Therefore, we concluded that Se levels in these systems are usually sufficient to limit disruption of selenoprotein activities by Hg, and that fish consumption advisories based on Hg alone are unnecessarily restrictive.