Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in combination with PLD were assessed. (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed for early response monitoring. Nineteen patients with advanced breast, endometrial, and ovarian cancer were treated with increasing doses of temsirolimus (10, 15, or 20 mg once weekly) and PLD (30 or 40 mg/m(2) once every 4 weeks). PLD was initiated 2 weeks after start of temsirolimus. FDG-PET/CT was performed at baseline, after 2 and 6 weeks. Standardized uptake values (SUV), metabolic volume, and total lesion glycolysis (TLG, SUV x metabolic volume) were calculated. The RPTD was 15 mg temsirolimus and 40 mg/m(2) PLD. Dose-limiting toxicities (DLT) were thrombocytopenia grade 3 with nose bleeding and skin toxicity grade 3. Most frequent treatment-related toxicities were nausea, fatigue, mucositis, and skin toxicity. Changes in TLG after 2 weeks predicted partial response (PR) after 10 weeks (p = 0.037). A rise in SUV between the second and sixth week predicted progression (PD) (p = 0.034) and was associated with worse progression free survival (PFS) (HR 1.068; p = 0.013). The RPTD was established at 15 mg temsirolimus weekly and PLD 40 mg/m(2) once every 4 weeks and the combination was safe. Early response evaluation with FDG-PET/CT may predict subsequent radiological PR and PD. This trial is registered under number NCT0098263.