Shukla, J., Chatterjee, S., Thakur, V. S., Premachandran, S., Checker, R. and Poduval, T. B. l-Arginine Reverses Radiation-Induced Immune Dysfunction: The Need for Optimum Treatment Window. Radiat. Res. 171, 180–187 (2009).The aim of the present study was to investigate the protective efficacy of l-arginine in mitigating the injury induced by 2 Gy of total-body γ radiation (TBI). Mice exposed to radiation (TBI group) had significantly decreased spleen weight, splenocyte numbers and bone marrow cellularity. Administration of l-arginine 2 h after TBI (TBI l-arginine group) was effective in reducing the radiation-induced depletion of spleen and bone marrow cellularity but was not effective when administered before TBI (l-arginine TBI group). The radiation-induced decrease in Con A-induced spleen cell proliferation, specific antibody response of spleen B cells to sheep red blood cells, and spleen RNA content was reversed in mice in the TBI l-arginine group. The radiation-induced increase in serum TNF-α levels, serum nitrate/nitrite (NOx) levels, spleen DNA fragmentation, spleen nitric oxide synthase (NOS) activity, spleen inducible NOS (iNOS) activity, and hepatic iNOS activity was reversed in mice in the TBI l-arginine group. l-Arginine administered before TBI could not reverse these changes. Mice in the TBI l-arginine group had significantly increased spleen arginase activity compared to mice from either the TBI or l-arginine TBI group. The results suggest the importance of the time of administration of l-arginine and the l-arginine pathway in mitigating the radiation-induced host immune dysfunction.