Background: TGF-β shifts from inhibition to stimulation of vascular smooth muscle cell (vSMC) growth when cell density increases. How proliferation and apoptosis contribute to this shift is still unknown. Methods: In sparse and confluent V8 vSMC treated or not with TGF-β<sub>1</sub> (1 ng/ml) for 3 days, cell number, mitotic activity, cell-cycle-regulatory protein levels, caspase-3 and phosphoinositide 3-kinase (PI3-K) activities were studied. Results: In TGF-β<sub>1</sub>-treated cells, (i) the growth curve rose constantly compared to controls, reaching post-confluent densities; (ii) mitotic activity, which was constant at all cell densities, was lower than in sparse but higher than in contact-inhibited control cells, and (iii) apoptosis occurred at sparse densities only. The mechanism of proliferation control by TGF-β<sub>1</sub> was very unconventional in V8 vSMCs: (i) p15<sup>INK4b</sup> and cyclin D levels were similar in cells treated or not with TGF-β<sub>1</sub>, and (ii) p27<sup>Kip1</sup> levels remained very low even at high densities while cyclin E levels were not markedly decreased. TGF-β<sub>1</sub>-induced apoptosis in sparse cultures and its reversal in dense cultures were inversely correlated to PI3-K activation. Conclusions: TGF-β<sub>1</sub> slowed sparse V8 vSMC growth by inhibiting proliferation and inducing apoptosis. TGF-β<sub>1</sub>-treated confluent vSMCs escaped contact inhibition and kept growing through unconventional regulation of p27<sup>Kip1</sup>, cyclin E and suppression of apoptosis.