Exposure of a myeloma cell line (RPMI 8226) to a 30-minute pulse of melphalan (1-phenylalanine-mustard) resulted in a cell cycle progression delay characteristic for DNA cross-linking agents. Reduction of outflow of cells from late S- and G2-phases was more pronounced as compared to that from G1-phase. The consequence is a progressive accumulation of cells in late S- and G2-phases. At restoration of outflow of cells from late S- and G2-phases, complete removal of DNA interstrand cross-links, as measured by DNA alkaline elution, was noted. At this time less than 50% of maximum DNA-protein cross-links were removed. Further we found no correlation between restored outflow of cells from the G2-phase and removal of DNA-protein cross-links during the follow-up time of 72 h. No DNA double strand breaks as measured by DNA neutral elution were formed during the observation period. The data suggest that removal of DNA interstrand cross-links seems prerequisite for the outflow of cells from G2 after melphalan treatment.