Alkaline phosphatase (ALP) flare phenomenon documented as scintigraphic flare phenomenon due to elevated serum ALP levels produced by osteoblasts reflects an osteoblastic reaction in response to the effective therapy of non-small cell lung cancer (NSCLC). Here, we report a case of ALP flare following gefitinib treatment for NSCLC. We also retrospectively analyzed the prevalence of ALP flare in lung cancer patients treated via epidermal growth factor receptor-tyrosine kinase inhibitor in our hospital. Recognition of this phenomenon is important for physicians treating NSCLC patients to avoid discontinuation of a potentially beneficial treatment because of misdiagnosis for refractory multiple bone metastasis or adverse effect.