Apart from the well-documented effect of fluoride in drinking water on dental caries, little is known about other chemical effects. Since other ions in drinking water may also theoretically influence caries, as well as binding of fluoride in the oral environment, we hypothesized that the effect of drinking water on caries may not be limited to fluoride only. Among 22 standard chemical variables, including 15 ions and trace elements as well as gases, organic compounds, and physical measures, iterative search and testing identified that calcium and fluoride together explained 45% of the variations in the numbers of decayed, filled, and missing tooth surfaces (DMF-S) among 52,057 15-year-old schoolchildren in 249 Danish municipalities. Both ions had reducing effects on DMF-S independently of each other, and could be used in combination for the design of optimal drinking water for caries control in populations.