Aim Determination of piperaquine (PQ) in pediatric plasma requires a method with a small sample volume. Results We report a sensitive LC–MS/MS method for quantitation of PQ with only 25 µI human plasma. Using a deuterated internal standard (PQ-d6), an analytical PFP column, APCI+ as the ion source and MRM (535/288 for PQ and 541/294 for the IS) for detection, the method has a linear calibration range of 1.5–250 ng/ml with a runtime of 3.0 min per sample. The method was applied to plasma samples from children. Conclusion The developed LC–MS/MS method is suitable for pediatric studies with small volume plasma samples collected via capillary tubes. One limitation was the performance of PFP columns varied among different brands.