Patients with a suspected connective tissue disorder should undergo serologic testing to confirm the diagnosis and, in some cases, to monitor disease activity and predict flares. Patients with suspected systemic lupus erythematosus should be tested for antinuclear antibodies. However, antinuclear antibodies are not specific and may be present in many other connective tissue disorders and nonrheumatologic diseases. Thus, patients with suspected systemic lupus erythematosus should undergo further testing to confirm the diagnosis. Patients with Sjogren syndrome may have a positive antinuclear antibody titer, but often also have positive anti-Sjogren antigen A or B results. Similarly, antinuclear antibodies can be present in patients with scleroderma, mixed connective tissue disease, and dermatomyositis or polymyositis. Additional tests are needed to help confirm the diagnosis. In patients with findings of rheumatoid arthritis, a positive rheumatoid factor titer suggests the diagnosis, but as with antinuclear antibodies, it is not specific and can occur in other conditions. Rheumatoid factor can also be negative in patients with rheumatoid arthritis. A positive anticyclic citrullinated peptide antibody titer is more specific for rheumatoid arthritis and can help confirm the diagnosis. Physicians should order these serologic tests only when patients have a high pretest probability of a specific connective tissue disorder. Copyright (C) 2018 American Academy of Family Physicians.