The objectives of this study are to highlight the arthritic presentation of acute lymphoblastic leukemia (ALL) in children and to delineate features that could help differentiate it from juvenile idiopathic arthritis (JIA). We present a retrospective case control study based on records of the Pediatric Rheumatology Clinic, Advanced Pediatric Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India for the period January 2005-October 2008. We compared the clinical profile of 11 children referred to us with musculoskeletal complaints who were ultimately diagnosed to have ALL, with the clinical profile of an equal number of age and sex matched children with JIA. Important features that predicted a diagnosis of ALL and differentiated it from JIA were history of night pain (P = 0.001), non-articular bony pain (P = 0.001), presence of joint pain out of proportion to physical findings (P = 0.0001), anemia (P = 0.004), leucopenia (P = 0.045), lymphocytic predominance (P = 0.002) and thrombocytopenia (P = 0.012). In conclusion, children with musculoskeletal complaints are often referred to the rheumatologist for evaluation. The treating physician should always exclude the possibility of an underlying ALL especially if there are atypical clinical features or subtle hematological abnormalities.