Geriatric patients with acute infection show increased muscle weakness and fatigability but the relative contribution of central and peripheral factors is unclear. Hospitalised patients with acute infection (82 ± 6 years, N = 10) and community-dwelling controls (76 ± 6 years, N = 19) sustained a maximal voluntary isometric contraction of the M. Adductor Pollicis until strength dropped to 50% of its maximal value. Voluntary muscle activation (VA) was assessed before and at the end of the fatigue protocol using twitch interpolation method and muscle activity was monitored using surface electromyography. Twenty-five circulating inflammatory biomarkers were determined. At pre-fatigue, no significant difference in VA was found between groups. VA decreased to similar levels (˜50%) at the end of the fatigue protocol with no association with inflammatory biomarkers. In geriatric patients, muscle activity decreased significantly (p < 0.05) during the fatigue protocol, whereas it increased in the controls (time * group interaction p < 0.05). The decrease in muscle activity was significantly related to higher levels of inflammation. Although slower muscle contraction and relaxation were significantly related to higher levels of inflammation, no statistical differences were found between groups. Our results confirm that muscle activity is significantly altered in older patients with acute infection and that local processes are involved.