A national cooperative group trial was conducted in 153 patients with chronic myelogenous leukemia (CML) in chronic phase treated with oral pulse busulfan to determine if oral vitamin A can increase the time to blast crisis and enhance survival of patients. Patients diagnosed within 1 year and in the chronic phase of CML were randomized to receive oral pulse busulfan or the alkylator plus continuous oral vitamin A. Distributions of clinical progression and overall survival were estimated using the method of Kaplan and Meier. Associations of these endpoints with treatment and other patient characteristics were analyzed using the proportional hazards regression method of Cox. Both regimes were well tolerated. Patients in the busulfan plus vitamin A arm had somewhat longer durations of clinical progression-free survival (median 46 months) and overall survival (51 months) compared to those in the busulfan arm (medians 38 and 44 months). However, the differences were not statistically significant (one-tailed P = 0.11 for clinical progression-free survival, 0.081 for survival). After adjustment for significant factors identified in an additional exploratory multivariate analysis, risk of clinical progression or death was 53% (P = 0.022) greater and risk of death 60% (P = 0.014) greater among busulfan patients. Given the relatively large though non-significant difference between treatment arms, the limited statistical power of the study, and the likelihood that oral vitamin A may not be the most effective means of delivering retinoid therapy, we conclude that further investigation of retinoids in chronic phase CML is warranted.