OBJECTIVES: Few studies have examined the longitudinal course of Primary (idiopathic) Restless Legs Syndrome (P-RLS), a sensorimotor neurological disorder characterized by an urge to move that is usually associated with unpleasant sensations in the leg. We conducted a large-scale retrospective claims analysis to compare 2-year antecedent versus subsequent diagnoses of newly diagnosed patients with P-RLS. METHODS: From 5-year (7/1/2008-6/30/2013) MarketScan Commercial and Medicare Supplemental claims databases, selected patients had ≥1 RLS claim (ICD-9 333.94) and ≥2 years preceding and following their first (Index) RLS diagnosis. Excluded were patients ever diagnosed with Parkinson’s (ICD-9 332) or kidney disease (ICD-9 403-404, 584-585, 669.3, 996.81, V42.0; CPT 90951-90970; HCPCS A4690, A4653, E1510, E1530-40, E1570-E1632, G0420-21, J2150, S2065), iron deficiency (ICD-9 280), or pregnancy (ICD-9 630-679). McNemar’s test identified statistically significant changes in percent of patients receiving diagnoses from Pre- versus Post-Index Periods. Logistic regression examined odds ratios (OR) and 95% confidence intervals (CI) for significant findings (≤0.05). RESULTS: Among 10,484 patients satisfying study criteria, the likelihood of receiving diagnoses in the Post- versus Pre-Period increased significantly for: Mental Disorders (ICD-9 290-319) in outpatient (OR 1.3, 95%CI 1.2-1.4, p<0.0001), inpatient (OR 1.7, 95%CI 1.3-2.3, p=0.0005), and emergency department (ED) (OR 1.4, 95%CI 1.1-1.8, p=0.0013) settings; Circulatory System Disorders (ICD-9 390-459) in outpatient (OR 1.4 95%CI 1.3-1.5, p<0.0001), inpatient (OR 1.2, 95%CI 1.0-1.4 p<0.0426), and ED (OR 1.5, 95%CI 1.3-1.7, p<0.0001) settings; and Musculoskeletal and Connective Tissue Diseases (ICD9-710-739) in outpatient (OR 1.3, 95%CI 1.2-1.3, p<0.0001), inpatient (OR 1.4, 95%CI 1.3-1.6, p<0.0001), and ED (OR 1.2, 95%CI 1.1-1.4, p=0.0021) settings. CONCLUSIONS: Among newly-diagnosed P-RLS patients, compared to the Pre-Index Period, the likelihood of receiving diagnoses in outpatient, inpatient and ED settings for Mental, Circulatory System, or Musculoskeletal and Connective Tissue disorders in the Post-Index Period significantly increased. Whether findings represent initial misdiagnoses, disease progression, or treatment effects remains unknown.