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Objective: Systemic lupus erythematosus (SLE) presents with nonspecific signs and symptoms that are also found in other conditions. This study aimed to evaluate manifestations at disease onset and to compare early SLE manifestations to those of diseases mimicking SLE. Methods: Academic lupus centers in Asia, Europe, North America, and South America collected baseline data on patients who were referred to them during the previous 3 years for possible SLE and who had a symptom duration of <1 year. Clinical and serologic manifestations were compared between patients diagnosed as having SLE and those diagnosed as having SLE‐mimicking conditions. Diagnostic performance of the 1997 American College of Rheumatology (ACR) SLE classification criteria and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) SLE classification criteria was tested. Results: Data were collected on 389 patients with early SLE and 227 patients with SLE‐mimicking conditions. Unexplained fever was more common in early SLE than in SLE‐mimicking conditions (34.5% versus 13.7%, respectively; P < 0.001). Features less common in early SLE included Raynaud's phenomenon (22.1% versus 48.5%; P < 0.001), sicca symptoms (4.4% versus 34.4%; P < 0.001), dysphagia (0.3% versus 6.2%; P < 0.001), and fatigue (28.3% versus 37.0%; P = 0.024). Anti–double‐stranded DNA, anti–β2‐glycoprotein I antibodies, positive Coombs' test results, autoimmune hemolytic anemia, hypocomplementemia, and leukopenia were more common in early SLE than in SLE‐mimicking conditions. Symptoms detailed in the ACR and SLICC classification criteria were significantly more frequent among those with early SLE. Fewer patients with early SLE were not identified as having early SLE with use of the SLICC criteria compared to the ACR criteria (16.5% versus 33.9%), but the ACR criteria demonstrated higher specificity than the SLICC criteria (91.6% versus 82.4%). Conclusion: In this multicenter cohort, clinical manifestations that could help to distinguish early SLE from SLE‐mimicking conditions were identified. These findings may aid in earlier SLE diagnosis and provide information for ongoing initiatives to revise SLE classification criteria. [ABSTRACT FROM AUTHOR]