Significance MRI-guided high-intensity focused ultrasound (MR-HIFU) is noninvasive technology able to focally heat tumor tissue from hyperthermic up to ablative temperatures. Although ablative temperatures can be used to destroy cancerous tissue directly, adequate ablation of tumor margins is often impossible due to the vicinity of vital structures, leaving a potential source for local recurrence. Another therapeutic option in oncology is hyperthermia-triggered local drug delivery using MR-HIFU in combination with temperature-sensitive liposomes (TSLs). In this study, we compare different MR-HIFU treatment schemes comprising ablation and hyperthermia-triggered drug delivery with respect to drug distribution and therapeutic efficacy. We show that a combination protocol of hyperthermia-induced drug delivery followed by ablation resulted in a homogeneous drug distribution and the highest therapeutic effect.