This paper suggests an explanation for listeners’ greater tolerance to positive than negative mistuning of the higher tone within an octave pair. It hypothesizes a neural circuit tuned to cancel the lower tone, that also cancels the higher tone if that tone is in tune. Imperfect cancellation is the cue to mistuning of the octave. The circuit involves two neural pathways, one delayed with respect to the other, that feed a coincidence-sensitive neuron via excitatory and inhibitory synapses. A mismatch between the time constants of these two synapses results in an asymmetry in sensitivity to mismatch. Specifically, if the time constant of thedelayedpathway is greater than that of the direct pathway, there is a greater tolerance topositivemistuning than to negative mistuning. The model is directly applicable to the harmonic octave (concurrent tones), but extending it to the melodic octave (successive tones) requires additional assumptions that are discussed. The paper reviews evidence from auditory psychophysics and physiology in favor – or against – this explanation.