Background: Engraftment fever (EF) is common in 2^ndweek post autologous hematopoietic stem cell transplant (auto HSCT). It is difficult to differentiate from infective fever (IF). This leads to unnecessary use and cost of antibiotics. Also timely treatment of EF may prevent progression to full blown engraftment syndrome (ES). We studied the role of total leucocyte count (TLC) to C-reactive protein (CRP) ratio in differentiating EF from IF. Methods: Consecutive patients with breakthrough fever (BF) from d+7 to d+15 post auto HSCT, from March 2011 to August 2013, were included in this retrospective analysis. BF was defined as new onset fever preceded by an afebrile period of at least 48 hours. BF episodes were classified as IF or EF. Fever was classified as IF if blood culture was positive, or there were radiological signs of infection or if fever subsided within 48 hours of change of antibiotics. EF was defined as fever associated with rising counts without any identifiable infective focus responding to steroids. Antibiotics were added at the onset of BF. If fever persisted beyond 48 hours and no infective cause was identified, systemic steroids were started. Daily morning TLC and CRP values were obtained from patients’ records. TLC:CRP ratio was calculated from day of admission to day of discharge. Optimal cut-off value of the ratio on the day of BF was obtained by plotting a receiver operating curve. Sensitivity and specificity were calculated. Results: Seventy patients had BF of 110 auto HSCT patients. Nineteen had multiple myeloma, 50 had lymphoma and 1 neuroblastoma. Median day of neutrophil and platelet engraftment was 10 and 13 respectively. The median day of BF was 9. Sixty two patients had EF, among whom 15 had ES. We found an optimal value of 0.056 for differentiating between IF and EF. Using a ratio > 0.056 for diagnosing EF, sensitivity and specificity were 63% (95% CI – 50 – 75%) and 100% (95% CI – 63 – 100%) respectively. Conclusions: In 2^nd week post auto HSCT, a value of the ratio of TLC:CRP > 0.056 on the day of BF is highly specific for EF. Prospective studies are warranted to confirm the results. This could help reduce unnecessary use and cost of antibiotics.