Background: Acute rheumatic fever (ARF) continues to be a public health problem in low- and middle-income countries. Because there is no specific laboratory test for the exact diagnosis of ARF, the diagnosis is made by the modified Jones criteria. Periostin is an extracellular matrix protein which has been shown to be expressed during remodelling, mechanical stress and tissue repair. There are no data on the relationship between periostin and ARF. Aim: To evaluate serum periostin levels in patients with ARF and investigate its usefulness as a biomarker for diagnosing and monitoring the efficacy of treatment. Methods: Serum periostin levels were estimated in 31 patients with ARF and compared with a control group of 25 healthy patients. The control group comprised patients referred to the outpatient clinic for further evaluation of cardiac murmur, palpitations or chest pain. Patients who were diagnosed with any other cardiac or systemic illness after detailed systemic and cardiac examination were excluded. Results: The mean (SD) age at diagnosis was 12.1 (3.3) years in the patient group, 48.4% of whom were male. There were no significant differences in age or gender between patients and controls. All the study patients had various degrees of carditis, 58.1% had arthritis and 9.6% had Sydenham chorea. Mean (SD) serum periostin levels in patients with ARF on admission [58.4 (13.9) ng/mL] were significantly higher than in the control group [35.1 (10.7) ng/mL, p < 0.01] and were also significantly decreased in the patient group after treatment [35.1 (13.1) ng/mL, p < 0.01]. There was no significant difference in serum periostin levels regarding the severity of carditis in the patient group while patients with any severity of carditis had significantly higher periostin levels than the controls (p < 0.01). Periostin levels were significantly correlated with ESR and CRP values before treatment, but this correlation was detected for only ESR after treatment. For the initial diagnosis of ARF, a serum periostin level of 53.45 ng/mL was found to be the cut-off point with 80.6% sensitivity and 100% specificity. Conclusion: There was a significant increase in serum periostin levels in patients with ARF and a reduction after adequate treatment which was independent of the severity of carditis. Periostin may be a biomarker which acts as an acute phase reactant in ARF.