This phase I trial evaluated the toxicity profile and maximum tolerated dose of the combination between the marine derived cyclodepsipeptide plitidepsin and bevacizumab in advanced cancer patients. Thirteen patients were enrolled and treated with plitidepsin at three dose levels (2.8 mg/m2, n=3; 3.8 mg/m2, n=4; and 4.8 mg/m2, n=6) with a fixed dose of bevacizumab (10 mg/kg). Both agents were administered intravenously at D1 and D15 of a 28-day cycle. All 13 patients were evaluable for safety and toxicity. Dose-limiting toxicities occurred in two out of six patients treated at the maximum dose tested (plitidepsin 4.8 mg/m2 and bevacizumab 10 mg/kg) and consisted of grade 3 fatigue, grade 3 myalgia, and two grade 2/3 alanine aminotransferase increases lasting for more than 7 days or leading to subsequent cycle delay greater than 2 weeks (n=1 each). The recommended dose for the combination of plitidepsin with bevacizumab was 3.8 mg/m2 for plitidepsin and 10 mg/kg for bevacizumab every 2 weeks. Most frequent treatment-related adverse events were nausea, vomiting, fatigue, epistaxis, and headache. Relevant hematological toxicity was minimal. Objective disease responses were not observed; however, stable disease (>3 months) was observed in four patients with colorectal cancer, renal cancer, and cervical cancer. Combining plitidepsin with bevacizumab combination is feasible. Stable disease was the best response obtained.