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Background: Scrub typhus, caused by Orientia tsutsugamushi infection, is one of the main causes of febrile illness in the Asia-Pacific region. Although cell-mediated immunity plays an important role in protection, little is known about the phenotypic changes and dynamics of leukocytes in scrub typhus patients. Methodology/Principal Findings: To reveal the underlying mechanisms of immunological pathogenesis, we extensively analyzed peripheral blood leukocytes, especially T cells, during acute and convalescent phases of infection in human patients and compared with healthy volunteers. We observed neutrophilia and CD4+ T lymphopenia in the acute phase of infection, followed by proliferation of CD8+ T cells during the convalescent phase. Massive T cell apoptosis was detected in the acute phase and preferential increase of CD8+ T cells with activated phenotypes was observed in both acute and convalescent phases, which might be associated or correlated with elevated serum IL-7 and IL-15. Interestingly, peripheral Treg cells were significantly down-regulated throughout the disease course. Conclusions/Significance: The remarkable decrease of CD4+ T cells, including Treg cells, during the acute phase of infection may contribute to the loss of immunological memory that are often observed in vaccine studies and recurrent human infection. Author Summary: Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi infection. It has been estimated that one billion people are at risk and one million new cases arise each year in Asian-pacific region. Despite of aggressive attempts to develop a prophylactic vaccine against scrub typhus during the last several decades, all approaches have failed to generate long lasting immunity. In addition, little is known about the immunological pathogenesis of scrub typhus. To understand the pathogenic mechanisms of this infectious disease, we extensively analyzed peripheral leukocytes, especially T cells, in Korean scrub typhus patients and compared with healthy volunteers. We observed neutrophilia and CD4+/T lymphopenia in the acute phase of infection, followed by proliferation of CD8+ T cells during the convalescent phase. Massive T cell apoptosis was detected in the acute phase and a preferential increase of CD8+ T cells with activated phenotypes was observed in both acute and convalescent phases. The remarkable decrease of CD4+ T cells, including Treg cells, during the acute phase of infection may contribute to the loss of immunological memory and generate helpless but unregulated cytotoxic T cell responses observed in vaccine studies and recurrent human infection. [ABSTRACT FROM AUTHOR]