Nervous system dysfunction may occur in as many as 80% of patients with Systemic Lupus Erythematous (SLE) at some point in their disease course. Upregulation of adhesion molecules has been linked to acute SLE-related disease activity and chronic damage. We evaluated the relationship between soluble adhesion molecule levels and neuropsychiatric lupus (NPSLE) manifestations using the American College of Rheumatology (ACR) case definitions to investigate for evidence of a link between upregulation of adhesion molecules and NPSLE manifestations. Sera from the initial study visit of 133 SLE patients enrolled in the San Antonio Lupus Study of Neuropsychiatric Disease (SALUD) and 40 controls were evaluated for soluble adhesion molecule levels (VCAM-1, ICAM-1 and E-selectin) and antiphospholipid antibodies. A subset of 57 SLE patients were evaluated for soluble adhesion molecule levels and antiphospholipid antibodies on two subsequent study visits, as well. NPSLE manifestations at the time of sera ascertainment were recorded using ACR case definitions and SLE-related acute activity and damage were measured. Elevated levels of all three soluble adhesion molecules were seen in SLE patients compared to normal control values. Soluble VCAM-1 levels correlated with measures of current disease activity, NPSLE manifestations and deep venous thrombosis. Persistently positive levels of ICAM-1 and VCAM-1, but not E-selectin were association with increased SLE-related damage. Elevated levels of all soluble adhesion molecule levels correlated with abnormal levels of antiphospholipid antibodies, which are associated with some NPSLE manifestations and have been shown to upregulate adhesion molecule expression.