Using carbon fiber amperometry, we exploited the natural variation in quantal size (Q) among individual granules in rat chromaffin cells to examine the influence of Q on quantal release kinetics. Although it is generally accepted that granules with larger Q have slower kinetics of release, we found that this trend was applicable only to granules with Q1/3 < 0.6 pC1/3. Granules with larger Q adapted specific mechanisms to maintain a rapid kinetic of release. The semistable fusion pores in the large-Q granules persisted for a longer duration and could reach a bigger size before the onset of very rapid dilation to allow a longer and larger foot signal. Most importantly, a large proportion of large-Q granules maintained a relatively short half-width in the main spike. This suggests that the most rapid phase of fusion pore dilation in many large-Q granules may be faster than that in small-Q granules. Moreover, cAMP selectively advanced the onset of the rapid dilation of the fusion pore in the large- but not the small-Q granules. Thus, our finding raises the possibility that fusion pore and/or granule matrix in small- and large-Q granules may have different molecular structures.