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Background: Malnutrition is a public health problem in the entire world, particularly in the developing countries. The effect of Spiruline supplement in the weight recovery of HIV-negative and HIV-infected undernourished children has been largely demonstrated. The aim of this study is to determine the effect of Spiruline on the immune status of 46 HIV-infected undernourished children, aged 15 ± 5 months, and of 23 undernourished HIV-negative children, aged 14 ± 6 months.Methodology: The duration of this study was eight weeks. To assess immune functions a count of CD4 lymphocyte subpopulation was performed before and after introducing the Spiruline supplement.Results: The degree of anemia improved in all the children, but the effect was less evident among HIV-infected children; in fact, 81% of HIV-negative versus 62% of HIV-infected children showed signs of improvement. The mean values of CD4 lymphocyte subpopulation showed a consistent increment in HIV-negative children [from 1257 (range 531-2301) to 1562 (range 798-2552) mm3] while they showed an irregular increase in HIV-infected children [from 1339 (152-4000) to 2088 (244-4214) mm3].Conclusions: The improvement of the immunological status due to Spiruline treatment might represent an effective barrier against infectious diseases, which both cause and result from malnutrition in underdeveloped countries.