An alternative liquid chromatography-mass spectrometry (LC-MS) method based on no discharge (ND) atmospheric pressure chemical ionization (APCI) was developed for the simultaneous determination of ethyl glucuronide (EtG) and ethyl sulfate (EtS) in urine in negative ion conditions. Abundant [M-H](-) species of EtG and EtS were obtained, allowing to reach limits of quantification (0.1 microg/ml for both analytes), accuracy, and precision comparable to those proposed in the literature. Additionally, the LC-ND-APCI-MS method proved to be reliable, requiring little maintenance even when high throughput analyses (i.e., 6,000 samples per year) were required.