Highly polar chemicals are mobile in an aqueous environment. Analytical methods for these compounds in water are lacking. A combined target/nontarget screening method based on hydrophilic interaction LC coupled to high-resolution MS was developed. Thirty-two highly polar chemicals (including melem and melam) can thus be quantitatively measured in surface water and drinking water, and the MS data can be screened for unknown compounds. This is the first time a method for the determination of melem and melam in water has been described. The method is complementary to existing target and nontarget methods for less polar substances and can be applied for (drinking) water quality assessment. In a screening study in The Netherlands and Flanders, 12 of the 32 compounds were encountered in groundwater, surface water, and drinking water at levels between 0.01 and 4.2 μg/L. Concentrations in drinking water were compared with (provisional) guideline values to assess whether these may pose a concern for human health. In one drinking water sample, the concentration of dichloroacetic acid exceeded the provisional guideline value, indicating that health effects cannot be excluded on the basis of lifetime exposure. For most chemicals, reliable drinking water guideline values could not be derived due to the limited available of toxicity data.