Current alternative therapies for refractory thyroid cancer such as kinase inhibitors have limitations including incomplete response and toxicity. Although tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell-specific apoptosis, various degrees of TRAIL resistance have been reported for different types of thyroid cancer cells. Here, we investigated if modulation of autophagy could improve sensitivity to TRAIL in papillary and anaplastic thyroid cancer cells. Human papillary thyroid cancer cells (TPC-1 cells) and human anaplastic thyroid cancer cells (FRO cells) were treated with TRAIL after transfection with ATG7 siRNA or control siRNA. Levels of autophagy and apoptosis were confirmed by Western blot of ATG7, LC3, caspase-3 and poly (ADP-ribose) polymerase. Viability index was determined by dimethyl-thiazole-diphenyltetrazolium bromide assay. Fraction of apoptotic cells was determined by flow cytometry. In TPC-1 cells, treatment with TRAIL increased the levels of autophagy. A low concentration (20 ng/ml) of TRAIL resulted in significantly decreased viability index and increased apoptosis. However, inhibition of autophagy with ATG7 siRNA desensitised the cells to TRAIL-induced apoptosis. In FRO cells, TRAIL did not increase the levels of autophagy. In contrast to TPC-1 cells, inhibition of autophagy with ATG7 siRNA sensitised FRO cells to TRAIL-induced apoptosis. Autophagy might contribute to the known sensitivity of papillary thyroid cancer cells to TRAIL-induced apoptosis. Inhibition of autophagy in anaplastic thyroid cancer cells could sensitise these cells to TRAIL-induced apoptosis.