Osimertinib is the cornerstone in the treatment of epidermal growth factor receptor-mutated non-small cell lung cancer (NSCLC). Nonetheless, ±25% of patients experience severe treatment-related toxicities. Currently, it is impossible to identify patients at risk of severe toxicity beforehand. We hence aimed to study the relationship between osimertinib exposure and severe toxicity, and to identify a safe toxic limit for a preventive dose reduction. In this real-life prospective cohort study, patients with NSCLC treated with osimertinib were followed for severe toxicity (grade ≥3 toxicity, dose reduction or discontinuation, hospital admission, or treatment termination). Blood for pharmacokinetic analyses was withdrawn during every out-patient visit. To quantify individual exposure to osimertinib, a population-pharmacokinetic model was developed. Primary endpoint was the correlation between osimertinib clearance (exposure) and severe toxicity. Secondary endpoint was the exposure-efficacy relationship, defined as progression-free (PFS) and overall survival (OS). In total, 819 samples from 159 patients were included in the analysis. Multivariate competing risk analysis showed osimertinib clearance (c.q. exposure) to be significantly correlated with severe toxicity (hazard ratio (HR) 0.93, 95% CI 0.88 – 0.99). An ROC-curve showed the optimal toxic limit to be 259 ng/mL osimertinib. This target concentration divides the cohort in two groups: the risk of severe toxicity in the >259 ng/mL group is 34% versus 14% in the <259 ng/mL group. A 50% dose reduction in the high-exposure group - i.e. 25.8% of the total cohort - would reduce the risk of severe toxicity by 53%. Correlation of the first plasma trough concentrations in collected in the first two months of treatment revealed a similar difference in severe toxicity (31% versus 17%), when dividing the cohort in two by the toxic limit of 259 ng/mL osimertinib. Osimertinib exposure was not significantly associated with PFS nor OS. Osimertinib exposure is highly correlated with occurrence of severe toxicity. To optimize tolerability, patients above the toxic limit concentration of 259 ng/mL could benefit from a preventive dose reduction, without fear for diminished effectiveness.