Nitric oxide (NO) is an important messenger molecule with multiple biological activities. In the present study, sper/NO, a NO generator, showed a biphasic effect on the proliferation of human salivary gland neoplastic (HSG) cells. Sper/NO of less than 20 lM stimulated cells to depart from the G2/M phase and so enhanced cell division and cell proliferation. But sper/NO at higher concentrations restrained cell proliferation and blocked cell-cycle progression. Cells were mainly arrested in the G2/M phase and S phase when they were treated with 100-200 and 300-500 lM sper/NO, respectively. Aspecial S-phase peak was detected in a histogram of the cell-phase distribution of sper/NO-treated HSG. When the concentration of sper/NO increased, the S-phase peak shifted from early the G2/M-phase to later the G1–S-phase boundary. Sper/NO-induced cell-cycle arrests were reversible when the cells were released from NO stress for 48 h and hence cell proliferation was recovered. In addition, micronucleus, but no apoptosis, was produced in the sper/NO-treated cells, and its yield tended to a saturation value with increasing concentrations of sper/NO. The sper/NO-induced effects were effectively eliminated or reduced by treating cells with PTIO, a NO-specific scavenger, indicating that NO is the main source of these effects.