Forty-four female patients who met the following criteria were studied. All were referred for rheumatology consultation because of symptoms and a positive antinuclear antibody (ANA) to rule out lupus. None fulfilled the American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE) at the time of the initial visit. All had a normal or noncontributory complete blood count, urinalysis, and blood panel. They lacked antideoxyribonucleic acid, anti-Smith (anti-Sm), antiribonucleoprotein (anti-RNP), anti-Ro, anti-La, and antiscleroderma 70 (anti-Scl-70) antibodies, and none had rheumatoid factor, elevated creatine phosphokinase levels, or decreased C3 complement or C4 complement values. We performed additional tests or procedures in an effort to improve diagnostic accuracy. Nine of 44 (20%) had a negative ANA on retesting. All patients were tested for antiribosomal P, antineuronal, antihistone-(H2A-H2B)/deoxyribonucleic acid complex antibody, anti-smooth muscle antibody and antithyroid antibodies, as well as Westergren sedimentation rate. Anticardiolipin antibody, serum protein electrophoresis, bone scanning, or skin biopsies with or without lupus band testing were obtained as clinically indicated. At the 6-month follow-up, 19 patients (43%) fulfilled the ACR criteria for SLE, 14 (32%) fulfilled the ACR criteria for fibromyalgia only, 4 (9%) had seronegative rheumatoid arthritis, 1 (2%) had myasthenia gravis, and 6 (14%) remained undiagnosed; 18/19 diagnosed with SLE had an additional antibody or positive diagnostic test listed above versus 3/25 without SLE (p<0.0001). Additional laboratory and diagnostic testing beyond the routine ANA profile correlated with the evolving diagnosis in 86% of the patients at 6 months.