【Objective】To establish a reliable HPLC-MS/MS (High performance liquid chromatography-tandem mass spectrometry) method suitable for determing tildipirosin residues in swine tissues.【Method】Swine tissue samples, including muscle, liver, kidney and skin-fat were extracted with 0.1 mol·L^–1 KH₂PO₄ buffer solution. The supernatant fluids were enriched and purified using HLB solid-phase extraction column, and gradiently eluted by Phenomenex Luna Omega C18 liquid chromatography column. The analytes were then detected using triple-quadrupole mass spectrometry in positive electrospray ionization and multiple reaction monitoring (MRM) mode. The matrix-matched method was used to calibrate tildipirosin content.【Result】Tildipirosin contents presented good linear relationships (r²>0.99) with characteristicion peak area in the ranges of 25–2 400 ng·g^-1 in muscle, 25–2 500 ng·g^-1 in liver, 25–2 000 ng·g^-1 in kidney and 25–1 600 ng·g^-1 in skin-fat. All the limits of detection and quantitation in muscle, liver, kidney and skin-fat samples added tildipirosin were 10 and 25 ng·g^-1, respectively. The recovery experiments of tildipirosin in swine tissues were setted in four dosage levels, including limit of quantitation, 1/2 maximum residue limit (MRL), MRL and 2MRL, and the mean intra-batch recoveries of tildipirosin in all analytes ranged from 85.6% to 105.0%. The relative standard deviations of intra-batch and inter-batch recoveries were in the ranges of 2.3%–9.5% and 4.7%–7.6%, respectively.【Conclusion】The established method is simple, practicable, and with high sensitivity and specificity. It can be applied to determine tildipirosin residues in swine tissues.