Background: Although blood flow restriction (BFR) is becoming increasingly popular in physical therapy and athletic training settings, little is known about the effects of BFR combined with low-intensity exercise (LIX) on muscles proximal to the site of occlusion. Hypothesis/Purpose: Determine whether LIX combined with BFR applied distally to the shoulder on the brachial region of the arm (BFR-LIX) promotes greater increases in shoulder lean mass, rotator cuff strength, endurance, and acute increases in shoulder muscle activation compared with LIX alone. We hypothesized that BFR-LIX would elicit greater increases in rotator cuff strength, endurance, and muscle mass. We also hypothesized that the application of BFR would increase EMG amplitude in the shoulder muscles during acute exercise. Study Design: Controlled laboratory study. Methods: 32 healthy adults were randomized into 2 groups (BFR group, 13 men, 3 women; No-BFR group, 10 men, 6 women) who performed 8 weeks of shoulder LIX (2 times per week; 4 sets [30/15/15/fatigue]; 20% maximum) using common rotator cuff exercises (cable external rotation [ER], cable internal rotation [IR], dumbbell scaption, and side-lying dumbbell ER). The BFR group also trained with an automated tourniquet placed at the proximal arm (50% occlusion). Regional lean mass (dual-energy x-ray absorptiometry), isometric strength, and muscular endurance (repetitions to fatigue [RTF]; 20% maximum; with and without 50% occlusion) were measured before and after training. Electromyographic amplitude (EMGa) was recorded from target shoulder muscles during endurance testing. A mixed-model analysis of covariance (covaried on baseline measures) was used to detect within-group and between-group differences in primary outcome measures (α = .05). Results: The BFR group had greater increases in lean mass in the arm (mean ± 95% CI: BFR, 175 ± 54 g; No BFR, –17 ± 77 g; P < .01) and shoulder (mean ± 95% CI: BFR, 278 ± 90 g; No BFR, 96 ± 61 g; P < .01), isometric IR strength (mean ± 95% CI: BFR, 2.9 ± 1.3 kg; No BFR, 0.1 ± 1.3 kg; P < .01), single-set RTF volume (repetitions × resistance) for IR (~1.7- to 2.1-fold higher; P < .01), and weekly training volume (weeks 4, 6-8, ~5%-22%; P < .05). Acute occlusion (independent of group or timepoint) yielded increases in EMGa during RTF (~10%-20%; P < .05). Conclusion: Combined BFR-LIX may yield greater increases in shoulder and arm lean mass, strength, and muscular endurance compared with fatiguing LIX alone during rotator cuff exercises. These findings may be due, in part, to a greater activation of shoulder muscles while using BFR. Clinical Relevance: The present study demonstrates that BFR-LIX may be a suitable candidate for augmenting preventive training or rehabilitation outcomes for the shoulder.