In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminthspecific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 moestimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (P time ) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) on CD4 + T cells of albendazoletreated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; P time = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low-compared with high-income countries.helminths | albendazole | cytokine responses | Indonesia | deworming S oil-transmitted helminths (STHs) represent the most common infectious disease worldwide (1). In addition to specific worm-associated morbidities, it has been argued that chronic STH infections may magnify health-related burdens in communities remote from health care facilities, exacerbating anemia, poor nutritional status, and possibly poor cognitive development (1). However, this was not fully supported by the latest analysis of the Cochrane database (2).Immunologically, cellular immune hyporesponsiveness is a hallmark of chronic helminth infections that may allow parasites' longterm survival (3). The consequences of immunosuppression are manifold with potentially major public health relevance. Immune hyporesponsiveness could curtail effective immune responses, thereby increasing susceptibility to pathogens, and helminths are associated with suboptimal vaccine responses (4-6). The helminthrelated dampened immune responses might nevertheless help to prevent immunopathology during coinfections and, possibly, aberrant reactivity to environmental or self-antigens (7). With respect to the latter, there is currently much interest in the use of helminth infections to treat allergies and autoimmune diseases, exploiting their ability to induce immune hyporesponsiveness (8).Suppressed lymphocyte responses were described in the 19...