Normal human cells of various types have a finite and predictable proliferative potential in vitro. This limited life span is due to a gradually increasing fraction of senescent cells that appear in the culture in a sudden and stochastic fashion due to a phenomenon referred to as sudden senescence syndrome (SSS). Because nondividing cells increasingly accumulate in the culture, dividing cells have to compensate for nondividers in order to accomplish additional population doubling (PD). Thus, individual dividing cells undergo more divisions, called cell generations (CG), than the number of PDs. Based on integrated experimental data, we calculated maximum CG for normal human diploid fibroblasts (HDF). It appears that for a HDF culture that undergoes 65 PD, the calculated final CG is at least 126. Based on the obtained value for CG we calculated the total size of the culture, both with and without effect of SSS. If no SSS takes place and cells divide by geometrical progression, the culture will grow up to 2(126) or 10(38) cells. By constantly eliminating cells from further divisions, causing cell loss (CL), SSS reduces the total size of the culture at every point during its proliferation. The calculated value for CL is enormous, so that the culture of 10(38) cells is reduced to only 10(19) cells, thus as little as 10(-17)% of its size! Accordingly, by preventing virtually every cell in the culture from reaching its original maximum doubling capacity, SSS appears to be the most important mechanism that influences cell culture proliferation.