Fully-sedated patients, being treated in the ICU, experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully-sedated ICU patients admitted for acute critical illness (n=3 males, n=3 females; age 63+/-6 y; APACHE II disease severity-score: 29+/-2). One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7+/-1 d while the other leg acted as non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fiber-type specific cross-sectional area (CSA). Furthermore, phosphorylation status of key proteins involved in the regulation of muscle protein synthesis was assessed, and mRNA expression of selected genes was measured. In the CON leg, type I and type II muscle fiber CSA decreased by 16+/-9 and 24+/-7%, respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mTOR phosphorylation by 19% when compared to baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined (FOXO1; P<0.05) or remained unchanged (MAFBx and MuRF1), with no differences between legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill, comatose patients.