Tipifarnib is a non-peptidomimetic farnesyl transferase inhibitor (FTI) with clinical activity in hematologic malignancies, including AML, MDS and CML. Pre-clinical data suggests that tipifarnib may be synergistic with some chemotherapeutic agents. We designed a phase I/II study where pts age 15 to 60 years with previously untreated AML or high-risk MDS (blasts >10%) received induction with Ida 12 mg/m2/d on days 1–3, ara-C 1.5 g/m2 IV over 24 hours daily on days 1–4 (days 1–3 only if age ≥ 60 years) and Z with first cohort (7 pts) receiving 200mg orally twice daily (BID), and all others 300 mg BID x 21 days every 28 days. Pts achieving CR received consolidation (5 courses) was with Ida 8 mg/m2/d, days 1–2, ara-C 0.75 g/m2/d, days 1–3, and Z 300 mg BID x14 days every 4–6 weeks. Maintenance was with Z 300 mg BID x 21 d every 4–6 wk for 6 months. We have treated 23 pts, median age 51 yrs (19–59 yrs). Eighteen pts are evaluable for response and 13 (72%) have achieved CR and 1 CRp. Response in evaluable pts by cytogenetics was: 5/8 (83%) for diploid, 4/5 with −5/−7, 1/2 with t(8;21), and 3/5 with other abnormalities. Response by Flt3 was 11/14 (79%) for unmutated Flt3, 1/3 for mutated Flt3. Response by age (excluding t(8;21)) was 6/7 (86%) if ≤50yrs, 7/9 (78%) if >50yrs. With median follow-up of 13 weeks, 1 pt has relapsed after 14 weeks and 1 died (in CR) after 18 wks. The most common grade 3 adverse events include diarrhea in 7 (30%) and hyperbilirrubinemia in 6 (26%), both transient. Thirteen pts (59%) have required treatment interruptions/dose reductions during induction. We conclude that Z combined with Ida and ara-C induces a high rate of CR in AML, with increased incidence of diarrhea and hyperbilirrrubinemia. Comparison with chemotherapy alone is warranted..