Acute lymphoblastic leukemia (ALL) presenting with musculoskeletal pain may be difficult to distinguish from juvenile idiopathic arthritis (JIA). The objective of this study, which separates it from most studies investigating these two diseases, is to determine the role of plain radiography in the initial approach toward patients presenting with musculoskeletal symptoms and to look for signs suggestive of each of the two disease entities. X-rays of patients referred to our center for musculoskeletal symptoms and ultimately diagnosed with JIA or ALL over a period of 10 years were studied retrospectively. The X-rays had been performed in the preliminary stage of the disease process and before the initiation of specific therapeutic measures. Soft tissue swelling, osteopenia, radiolucent metaphyseal bands, coarse trabeculation, and periosteal reactions were studied, and data analysis was performed by SPSS. Among a total of 174 patients, 118 had been diagnosed with JIA and 56 with ALL. The average age of JIA patients and ALL patients were 7.5 and 7.2 years, respectively. Soft tissue swelling was significantly more common among JIA patients (89.8%) than among those with ALL (1.8%) (P < 0.0001). Therefore, it is of the utmost importance to note the presence or absence of soft tissue swelling on plain radiography in the initial diagnostic approach. Osteopenia was seen in 60.2% of JIA patients compared with 14.3% of ALL patients (P < 0.0001). Radiolucent metaphyseal bands were seen among 7.1% of ALL cases but were notably absent in all cases of JIA. Coarse trabeculation was significantly higher in patients with ALL (7.1% ) than among JIA patients (0.8%). Periosteal reactions were seen in 6.8% of JIA group compared with 1.8% of ALL patients. We concluded that plain X-ray may be useful in selecting patients requiring bone marrow examination among those presenting with musculoskeletal symptoms mimicking JIA.