Synapses almost universally show a dependence of release probability on the recent history of activity: they facilitate or depress, and a number of mechanisms have been suggested to mediate this phenomenon, most prominent of which are delayed clearance of calcium ions from the presynaptic terminal and depletion of readily releasable vesicles. However, an intriguing phenomenon is revealed by several studies (e.g. [1]) that have looked at individual synapses with very short intervals between two presynaptic stimuli: the probability of observing a quantal release event is profoundly decreased on the second trial, not only when the first trial resulted in a release event, but also when the first trial resulted in a failure of release. The typical way that ‘release-independent depression’ is demonstrated is by repeatedly probing the synapse with paired stimuli, and sorting the results into several outcomes. Let us denote the probability of observing two failures as P(0,0), of observing a failure followed by a success as P(0,1), a success followed by a failure as P(1,0), and two successes as P(1,1). The reported result is that the success rate for the second response, if the first trial resulted in a failure, is lower than the overall success rate for the first trial: P(0,1)/(P(0,0)+P(0,1)) < P(1,0)+P(1,1). Several mechanisms have been proposed to underlie this ‘release-independent depression’, including failure of action potential invasion and calcium channel inactivation, although none of these has been conclusively demonstrated. We argue here that release-independent depression may actually be an illusion, resulting from an unrealistic assumption that the initial state of the synapse is constant across all the trials. Indeed, it is commonly accepted that at single synapse probability of neurotransmitter release in response to an action potential is determined by the number of release ready vesicles (RRV), n, and by the average probability of release for a single RRV, Pves. Accumulating data suggest that instantaneous probability of release at a given synapse can fluctuate from trial to trial due to fluctuations in both n and Pves [2,3]. Taking into account these observations we used Monte-Carlo simulations to demonstrate that stochastic fluctuations in instantaneous probability of release can give rise to apparent release-independent depression as a result of sampling bias. The time course of the relationship between this apparent depression and inter-stimulus interval provides a window on the kinetics of state transitions of the release apparatus.