Background: We attempted to determine the frequency and clinical relevance of antinuclear antibody (ANA) testing and positive ANA test results in patients with cutaneous T-cell lymphoma (CTCL). Methods: A retrospective chart and computer record review was conducted to determine the frequency of ANA testing in CTCL patients and the rate of seropositivity. Patients with a positive ANA were further examined to define possible explanations of the positive test. Results: Of 381 patients with CTCL, 66 (17%) had ANA tests; 8 of these (12.1%) were found to have an ANA titer greater than or equal to 1:40. Of patients with a positive ANA test, one was found to have chronic cutaneous lupus erythematosus histologically and clinically mimicking CTCL. Others were found to have a comorbid connective tissue disorder, some had apparent drug-induced antinuclear antibodies, and some had no identifiable reason for a positive ANA test. Conclusion: ANA seropositivity does not appear to be increased in CTCL patients, and the ANA test remains a useful screening tool for differentiating between CTCL and connective tissue disorders. (J Am Acad Dermatol 1998;39:434-8.)