Pemetrexed has demonstrated activity in hepatocellular carcinoma (HCC) cell lines, and has a manageable toxicity profile in clinical trials, suggesting its potential as a treatment for HCC patients. A multicenter, Phase II community-based study was conducted to assess the response rate and toxicity profile of single-agent pemetrexed in first-line patients with advanced or metastatic HCC. Patients premedicated with folic acid, vitamin B(12), and dexamethasone were administered pemetrexed 600 mg/m(2) IV on day 1 of each 21-day cycle until disease progression. This nonrandomized study employed Simon's 2-stage design, enrolling 21 eligible patients in the first stage, stopping accrual if < or =2 responders were observed. Responses were four stable disease, 14 progressive disease, and three not evaluable: two had early toxicities (renal/liver failure, sepsis) and one was noncompliant. The most common grade 3 hematological toxicities were neutropenia 6 of 21 (29%) and thrombocytopenia 3 of 21 (14%); with no grade 4 toxicities. Thirteen patients died on-study: 12 PD and one liver failure; none were drug-related. The median survival was 5.2 months (range, <1-12.2). The planned second stage was cancelled, and the trial was closed owing to lack of response. While pemetrexed was tolerated in this patient population, it was not active.