Abstract: It is hypothesized that, besides increased free radical production, aging is a process also related to inflammation. Thus, female and male senescence-accelerated (SAMP8) and senescence-resistant (SAMR1) mice of 5 and 10 months of age were studied to assess this hypothesis. Plasma from these mice was processed to determine nitric oxide (NO), and pro-inflammatory [interleukin (IL)-1β, IL-2, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and granulocyte–macrophage colony-stimulating factor] and anti-inflammatory (IL-4, IL-5 and IL-10) cytokines. The results show the presence of an age-dependent increase in IFN-γ and TNF-α and a reduction in IL-2 levels, with minor changes in the remaining cytokines. Moreover, age was associated with a significant increase in NO levels. Chronic melatonin administration between 1 and 10 months of age counteracted the age-dependent production of pro-inflammatory cytokines and NO, reducing them to the levels found at 5 months of age. Melatonin also reduced the levels of the anti-inflammatory cytokines. The results of this study suggest the existence of an inflammatory process during aging and further support that melatonin behaves as an essential molecule against aging, for its anti-inflammatory properties together with its antioxidative role reported elsewhere.