This multicenter, single-arm, open-label non-randomized phase II trial (NCT00744991) was conducted in patients with recurrent/refractory mycosis fungoides (MF), stage IB-IVB, or Sézary syndrome (SS). A Simon two-stage design required 25 patients enrolled in stage 1 with ≥7 confirmed objective responses for expansion into stage 2. Patients were treated with oral enzastaurin (250 mg twice daily) until disease progression or intolerable toxicity. The primary endpoint was investigator-assessed response rate; secondary endpoints were time to objective response, response duration, time-to-progression, patient-reported pruritus, and safety/tolerability. Twenty-five patients were enrolled. A partial response was observed in one patient with MF. Median time-to-progression was 78 and 44 days in MF and SS, respectively. Self-reported pruritus relief and improved composite pruritus-specific symptom scores were documented in six and four patients, respectively. Enzastaurin was well tolerated with mostly grade 1-2 adverse events, mainly diarrhea and fatigue. There were two adverse event-related drug discontinuations with one possibly treatment-related.