It is well known that many stimulus parameters, such as sound location in the auditory system or contrast in the visual system, can modulate the timing of the first spike in sensory neurons. Could first-spike latency be a candidate neural code? Most studies measuring first-spike latency information assume that the brain has an independent reference for stimulus onset from which to extract latency. This assumption creates an obvious confound that casts doubt on the feasibility of first-spike latency codes. If latency is measured relative to an internal reference of stimulus onset calculated from the responses of the neural population, the information conveyed by the latency of single neurons might decrease because of correlated changes in latency across the population. Here we assess the effects of a realistic model of stimulus onset detection on the first-spike latency information conveyed by single neurons in the auditory system. Contrary to expectation, we find that on average, the information contained in single neurons does not decrease; in fact, the majority of neurons show a slight increase in the information conveyed by latency referenced to a population onset. Our results show that first-spike latency codes are a feasible mechanism for information transfer even when biologically plausible estimates of stimulus onset are taken into account.coding ͉ inferior colliculus ͉ mutual information ͉ sound localization T he first-spike latency has been shown to carry information in several sensory modalities, including the auditory (1, 2), visual (3, 4), and somatosensory (5-7) systems. However, most studies quantifying first-spike latency information assume that the brain has an independent reference for stimulus onset from which to extract latency. In the majority of situations, this independent onset reference does not exist; the need for a timing reference has caused some to question the ultimate feasibility of first-spike latency codes (8).A number of authors have suggested possible alternative latency measures (1,3,5,6), but few have actually compared the information contained in different onset references. Stecker and Middlebrooks (9) computed the information contained in the relative spike timing of pairs of simultaneously recorded neurons in auditory cortex, and Furukawa et al. (10) compared the median errors from neural-network estimates of location with similar data. In both cases, performance with relative-latency measures was worse than with an independent onset reference, presumably because using a single neuron as the onset reference increases the overall measurement jitter. Other authors (11-13) have investigated rank order codes, where information is conveyed by the relative order in which neurons fire. Jenison (14) has shown by using modeling and maximum likelihood techniques that correlation can, in principle, increase the information available in first-spike latency, provided the decoder knows the correlation structure. However, such location estimates get noisier when stimulus onset is estimate...