The p53 tumor suppressor pathway is activated by defective ribosome synthesis. Ribosomal proteins are released from the nucleolus and block Hdm2 that targets p53 for degradation. However, it remained elusive how abrogation of individual rRNA processing pathways contributes to p53 stabilization. Here we show that selective inhibition of 18S rRNA processing provokes accumulation of p53 as efficiently as abrogated 28S rRNA maturation. We describe hUTP18 as a novel mammalian rRNA processing factor that is specifically involved in 18S rRNA production. hUTP18 was essential for the cleavage of the 5'ETS leader sequence from the primary Pol I transcript, but dispensable for rRNA transcription. As maturation of the 28S rRNA was unaffected in hUTP18 depleted cells, our results suggest that the integrity of both, the 18S and 28S rRNA synthesis pathways, can be independently monitored by the p53 pathway. Interestingly, accumulation of p53 after hUTP18 knockdown required the ribosomal protein L11. Therefore, cells survey the maturation of the small and large ribosomal subunits by separate molecular routes, which may merge in an L11-dependent signalling pathway for p53 stabilization.