The genome of the human HL-60 promyelocytic leukemia cell contains amplified c-myc sequences and the transforming N-ras oncogene. The present study has monitored c-myc and N-ras expression in HL-60 cells during induction of myeloid and monocytic differentiation with dimethyl sulfoxide, hexamethylene bisacetamide, 12-O-tetradecanoylphorbol-13-acetate and 1,25 dihydroxy-vitamin D3. The results demonstrate that induction of HL-60 differentiation is associated with decreases in c-myc RNA, while there is little if any effect on expression of the N-ras gene. Although the diminution in c-myc expression occurred as an early event in the induction of HL-60 differentiation, the rate of decrease in c-myc transcripts varied with respect to cessation of proliferation. Thus, the appearance of the mature phenotype and loss of proliferative capacity are associated with declines in c-myc RNA, while these events appear to occur in the absence of significant alterations in N-ras expression.