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Alzheimer’s disease (AD), the most common form of dementia, afflicts about 50 million people worldwide. Currently, AD diagnosis is primarily based on psychological evaluation and can only be confirmed post-mortem. Reliable and objective biomarkers for prognosis and diagnosis have been sought for years. Together, tau and amyloid β 1–42 (Aβ42) in cerebrospinal fluid (CSF) have been shown to provide good diagnostic sensitivity and specificity. Additionally, phosphorylated forms of tau, such as tau pS181, have also shown promising results. However, the measurement of such markers currently relies on antibody-based immunoassays that have shown variability, leading to discrepant results across laboratories. To date, mass spectrometry methods developed to evaluate CSF tau and Aβ42are not compatible. We present in this article the development of a mass-spectrometry-based method of quantification for CSF tau and Aβ42in parallel. The absolute concentrations of tau and Aβ42we measured are on average 50 ng/mL (7–130 ng/mL) and 7.1 ng/mL (3–13 ng/mL), respectively. Analyses of CSF tau and Aβ42, in a cohort of patients with AD, mild cognitive impairment, and healthy controls (30 subjects), provide significant group differences evaluated with ROC curves (AUC(control-AD)and AUC(control-MCI)= 1, AUC(MCI-AD)= 0.76), with at least equivalent diagnostic utility to immunoassay measurements in the same sample set. Finally, a significant and negative correlation was found between the tau and Aβ peptides ratio and the disease severity.