Uncommon mutations account for 10-15% of epidermal growth factor receptor (EGFR) mutations in patients with non-small-cell lung cancer (NSCLC). Most of them are proved to be sensitive or resistant to EGFR-tyrosine kinase inhibitors (TKIs). However, there is insufficient evidence for other less common types of EGFR mutations, such as complex mutations. Here, we present a 65-year-old never-smoking male who was diagnosed with stage IV lung adenocarcinoma. A rare L833V/H835L complex mutation in exon 21 of EGFR was detected in plasma and pleural effusion by next generation sequencing (NGS). Afatinib was used as first-line therapy and showed very good efficacy. To date, the patient is still benefited from afatinib treatment for a total of 10 months, with no signs of disease progression. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before treatment in clinical practice, and afatinib could be a first-line treatment option in NSCLC patients harboring H833V/H835L mutations.