Background: Mechanical diagnosis and therapy (MDT) is a specific classification-based musculoskeletal examination and intervention system that uses repeated end range and sustained movement to classify patients into mechanical syndromes. Research has recently demonstrated increased prevalence, reliability, and efficacy of MDT syndromes in varied peripheral musculoskeletal populations. There is currently no research analyzing if predictive variables exist for establishing directional preference in peripheral joints, other than the wrist. The aim of this study was to examine the clinical application of predictive variables for establishing directional preference and spinal referral in patients with isolated peripheral joint pain. Case Description: Thirty-seven consecutive patients with isolated peripheral pain were evaluated and classified using MDT assessment. Secondary analysis of predetermined variables was performed for association with directional preference and identification of spinal referral in Derangement syndrome. Results: All 37 patients were classified using MDT assessment. Thirty-three (89.2%) were classified as Derangement syndrome: 17 as spinal Derangement (45.9%) and 16 as peripheral Derangement (43.2%). One peripheral derangement also had an underlying Articular Dysfunction. Additionally, there were four patients classified as Other (10.8%). Discussion: Historical and physical examination findings were analyzed to determine if there were associated variables of directional preference or spinal referral. Mechanical stress was found to be the most associated factor in predicting directional preference. No peripheral movement loss, paresthesia, and constant pain were more associated with spinal referral. These findings may lead to a greater understanding of peripheral MDT assessment, which may lead to increased identification of directional preference and improved patient outcomes.