Purpose: During exercise in supine posture or under microgravity in space, the gravity-dependent component of local blood pressure in leg muscles at upright posture can be simulated by lower body negative pressure (LBNP). We hypothesized that during resistive exercise LBNP favors oxygen availability in lower extremities, benefiting energy levels and performance of working muscles. Methods: In permutated crossover design, nine subjects performed a series of fifteen slow-paced concentric (4 s) and eccentric contractions (4 s) without or with 40 mmHg LBNP and 4 s pause between repetitions. The force at knee flexion was 6% of the one repetition maximum (1-RM) and gradually increased to 60% 1RM in the first half of the individual range of motion, subsequently remaining constant until full extension. Results: During the low force periods of continuous exercise, LBNP enhanced the refill of capillary blood measured by near infrared spectroscopy, amplifying the increase of total haemoglobin by about 20 µmol/l (p < 0.01) and oxyhaemoglobin by about 10 µmol/l (p < 0.01). During continuous exercise, LBNP induced a trend towards a lower EMG increment. This LBNP effect was not found when the periods of low forces at knee flexion were extended by 4 s pauses. Increased respiratory oxygen uptake (+ 0.1 l/min, p < 0.05) indicated overall enhanced muscle energy turn-over. Conclusions: Our results suggest stimulation of oxidative metabolism through LBNP enables working muscles to meet the energy demands of intense exercise. Further research is needed on the consequences for energy metabolism and the molecular control of growth and differentiation.