Musicians spend long hours of practice and performance to master their instrument. Clarinet players support their roughly 2-lb instrument on the right-hand thumb, which results in cumulative static loading of the arm. This posture in turn can cause discomfort and, in some cases, evolve into debilitating overuse injuries and pain throughout the right upper limb. Altering the thumb-rest position has been proposed as a way to alleviate this discomfort, although no quantitative research has been conducted on this issue. The purpose of this study was to address the impact of thumb-rest position on the neuromuscular control of holding the clarinet. Surface electromyographic recordings of superficial muscles that control the right thumb, wrist, and arm were taken during realistic playing tasks. Twenty clarinetists performed 10 held notes and 10 exercises on the three different thumb-rest positions. The notes and exercises were chosen to isolate specific elements of playing. We hypothesized that a high thumb-rest position would result in a significantly different balance of muscle activity than traditional and low thumb-rest positions. The patterns of muscle activity recorded among clarinetists were idiosyncratic, but for all players these patterns were influenced by the note(s) played and thumb-rest position, and thus the hypothesis was partially supported. Muscles that acted on the thumb and wrist were most influenced by thumb-rest position. These results support the notion that adjustment of thumb-rest position may be a useful way to alleviate discomfort in the supporting limb but must be evaluated for each individual.