A prospective study was undertaken to assess the radiotoxicity of accelerated particles, in pulmonary alveolar macrophages (AM). We evaluated the effects of a single dose (10-75 Gy) of an external low-energy (20 MeV) proton beam on cultured AM oxidative metabolism and phagocytic function. Macrophages are the first line of defense against invading pathogens and are known to generate superoxide anion (O₂), nitric oxide (NO), and mediators of antimicrobial and antitumoral defense mechanisms. We obtained AM by bronchoalveolar lavage from young (1-2 mo. old) and aged (9-12 mo. old) male Wistar rats. Cell viability, phagocytosis, O₂ and NO production in control and proton-irradiated cultured AM were evaluated. The effect of proton irradiation on cell viability was dose-dependent. The higher doses induced a dramatic decrease in viability in the aged population. Phagocytosis increased 1.3-1.4 fold in both populations irrespective of the dose delivered. Generation of O₂ was always higher in the aged population for all the doses assayed and showed no significant variation from the control values. In the young population a clear increase was observed with doses of 25 and 50 Gy. NO production in AM from young animals rose in a dose-dependent manner. Conversely, proton irradiation did not affect NO production in macrophages from aged animals. The results of this study demonstrate that AM isolated from young and aged rats are functionally different and show a distinct behavior when exposed to proton irradiation. These findings suggest that age may condition response and must be taken into account when accelerated particle-radiotherapy protocols are considered as a valid therapeutic option for the treatment of cancer. To the best of our knowledge, this is the first report comparing sham-irradiated and proton-irradiated young and aged AM.