Musculoskeletal (MSK) pain is common in children and adolescents, with an estimated prevalence ranging from 2 to 50 percent. MSK pain can affect physical, psychological, and social function and often prompts consultation with a physician. However, MSK pain is often nonspecific, which can make it difficult to arrive at an accurate diagnosis. MSK pain may be due to rheumatic or nonrheumatic causes. Nonrheumatic causes are more common, generally benign, and most often attributable to trauma, overuse, and normal bone growth. Rheumatic causes, such as inflammatory arthritis, are infrequent, generally chronic, and require accurate, timely diagnosis and effective intervention to prevent progression and long-term damage. Common rheumatic causes of childhood MSK pain include pediatric systemic lupus erythematosus (pSLE) and juvenile idiopathic arthritis (JIA). A complete history and physical examination is generally considered to be the best way to make a diagnosis of inflammatory arthritis. Physicians may request serological tests such as antinuclear antibody (ANA), rheumatoid factor (RF), and cyclic-citrullinated peptide (CCP) when children and adolescents are suspected of having inflammatory arthritis, despite the fact that the diagnostic performance, usefulness, and proper interpretation of these tests are uncertain in pediatric populations. This comparative effectiveness review summarizes the evidence on the test performance of ANA, RF, or CCP tests for pSLE and JIA in children with undiagnosed MSK pain. The report is intended for a broad audience including primary care physicians who may consider ordering these tests in a child with MSK pain, health payers who provide coverage for these tests, and parents or caregivers who want to know whether these tests can determine if their child does or does not have a particular disease. In order to better understand how the ANA, RF, and CCP tests perform in the clinical setting of a child with undiagnosed MSK pain, it is important to know the prevalence of MSK complaints (including MSK pain and joint swelling) in children who do not have JIA and pSLE. It is also important to be aware of the rate of false positives for these tests (i.e., the proportion of otherwise healthy children who have a positive ANA, RF, or CCP test). Appropriate interpretation of test performance also requires an understanding of the disease progression and changes in signs and symptoms in children with MSK pain who may or may not also have JIA or pSLE. In addition to providing this background information, the objectives of this report were to assess the test performance of ANA, RF, and CCP tests in children and adolescents with undiagnosed MSK pain and/or joint swelling compared with clinical diagnoses of pSLE and JIA; to explore the difference in test performance for accuracy modifiers including age, sex, race or ethnicity, comorbidities, and recent infections; and to evaluate the impact of test results on clinical decisionmaking and clinically important outcomes such as referrals, ordering of additional tests, clinical management, and anxiety experienced by children and parents.