Periodic breathing and apnea are common in preterm infants. However, infants usually do not breathe periodically with apnea all the time, they oscillate between periods of regular and periodic breathing. We wanted to know what the factors are, during regular breathing, that change in order to facilitate the appearance of periodic breathing and apnea. We studied 27 preterms infants [BW 1440±116g (Mean±SE); SW 1660±112g; GA 29±1 wk; PNA 45±3 d] referred to our laboratory for investigation of apnea. Respiratory pattern was measured using a flow-through system and observations were made during an epoch of regular breathing followed by a epoch of periodic breathing during quiet sleep. We found: 1) instantaneous ventilation did not change from the regular breathing epoch to the 10 breaths preceding periodic breathing (0.298±0.006 to 0.305±0.010 L·min-1·kg-1; p>0.5). However, there was a clear change in pattern of breathing with a decrease in VT (6.7±0.1 to 5.5±0.2 ml·kg-1; p<0.01) and an increase in frequency (46±1 to 61±2 breaths/minute; p<0.001). Inspiratory time and expiratory time also decreased[0.57±0.01 to 0.50±0.01 s; (p<0.01) and 0.84±0.08 to 0.63±0.02 s (p<0.001), respectively]; 2) TcPO2 decreased from 71±1 to 64±1 Torr (p<0.001) and saturation from 97±0.2 to 90±0.5% (p<0.001) during the same period; 3) TcPCO2 did not change (39±1 to 39±1 Torr; p>0.5); butΔPACO2 between breaths increased from nil during baseline to 4±0.2 just preceding respiratory periodicity. The findings suggest: 1) the appearance of periodic breathing and apnea is preceded by clear changes in breathing pattern towards a faster and shallower breathing, and progressive hypoxemia; and 2) increased ΔPACO2 in between breaths before periodic breathing suggests that respiratory pattern becomes oscillatory before complete apnea occurs. We speculate that these changes in respiratory pattern bring the oscillations in PCO2 close to the apneic threshold and eventually below, making periodicity possible.