BACKGROUND The clinical significance of antinuclear antibody (ANA) status in adults with dermatomyositis (DM) has yet to be fully defined. OBJECTIVE We compared the incidence of amyopathic disease, risk of malignancy, and clinical findings in ANA+ and ANA- patients with adult-onset DM. METHODS This was a retrospective cohort study of patients with ANA+ or ANA- adult-onset DM determined by enzyme-linked immunosorbent assay. RESULTS Of 231 patients, 140 (61%) were ANA+ and 91 (39%) were ANA-. Compared with the ANA- patients, the ANA+ patients had a lower frequency of dysphagia (15% vs 26% [P = .033]) and heliotrope rash (38% vs 53% [P = .026]). In all, 54 patients (23%) developed malignancy within 3 years of diagnosis of their DM; 11% of the ANA+ patients developed malignancy versus 43% of the ANA- patients (P < .001). There was a strong association between ANA positivity and lower likelihood of malignancy in multivariable analysis (odds ratio, 0.16; P < .001). Conversely, ANA positivity was not associated with amyopathic disease (odds ratio, 0.94; P = .87). CONCLUSIONS The retrospective nature of the study was a limitation. CONCLUSIONS In patients with adult-onset DM, ANA negativity is associated with increased likelihood of development of malignancy within 3 years of diagnosis of their DM. Particularly close follow-up and frequent malignancy screening may be warranted in ANA- individuals with DM.