Context: Neuromuscular electrical stimulation (NMES) combined with blood flow restriction (BFR) has been shown to improve muscular strength and size better than NMES alone. However, previous studies used varied methodologies not recommended by previous NMES or BFR research. Objective: The present study investigated the acute effects of NMES combined with varying degrees of BFR using research-recommended procedures to enhance understanding and the clinical applicability of this combination. Design: Randomized crossover. Setting: Physiology laboratory. Participants: A total of 20 healthy adults (age 27 [4] y; height 177 [8] cm; body mass 77 [13] kg). Interventions: Six sessions separated by at least 7 days. The first 2 visits served as familiarization, with the experimental conditions performed in the final 4 sessions: NMES alone, NMES 40% BFR, NMES 60% BFR, and NMES 80% BFR. Main Outcome Measures: Maximal voluntary isometric contraction, muscle thickness, blood pressure, heart rate, rating of perceived exertion, and pain were all recorded before and after each condition. Results: The NMES 80% BFR caused greater maximal voluntary isometric contraction decline than any other condition (−38.9 [22.3] N·m, P < .01). Vastus medialis and vastus lateralis muscle thickness acutely increased after all experimental conditions (P < .05). Pain and ratings of perceived exertion were higher after NMES 80% BFR compared with all other experimental conditions (P < .05). No cardiovascular effects were observed between conditions. Conclusion: The NMES combined with 80% BFR caused greater acute force decrement than the other conditions. However, greater perceptual ratings of pain and ratings of perceived exertion were observed with NMES 80% BFR. These acute observations must be investigated during chronic interventions to corroborate any relationship to changes in muscle strength and size in clinical populations.