A study has been made at the ultrastructural level of the effects of denervation and axotomy on the synapse population of the rat superior cervical ganglion. Superior cervical ganglia were subjected unilaterally to acute (survival, 48 h) or chronic preganglionic denervation (survival, 41–189 days) by cutting the cervical sympathetic trunk; in chronic denervation experiments regeneration of preganglionic nerve fibres into the ganglion was prevented by suturing the proximal (caudal) stump of the trunk into the sternomastoid muscle. In some chronic experiments the preganglionic denervation was combined with simultaneous crush axotomy of the major postganglionic branches of the ganglion, the internal and external carotid nerves (axotomized-denervated ganglia). Control observations were made in contralateral ganglia and in ganglia from normal rats. After excision and before fixation, ganglia were incubated briefly in the presence of 5-hydroxydopamine to label adrenergic vesicles. Chronic denervation caused a statistically significant 12% decrease from control values in the cytoplasmic minor axes of the principal ganglionic neurones; axotomy combined with chronic denervation led to a 6% increase in this dimension, which was not statistically significant. The minor axes of the neuronal nuclei did not differ significantly from control values in either type of experiment. Axotomy combined with denervation led however to a 36% decrease in the incidence of nucleated neuronal profiles per unit area of ganglion. Counts of synapses were made in the various classes of ganglia and their incidence was expressed per nucleated neuronal profile, to permit comparison within and between experiments. Normal and control ganglia showed a high incidence of synapses of preganglionic cholinergic type. Nerve terminal profiles and synapses containing small dense-cored vesicles, as distinct from the efferent synapses of small granule-containing cells, were not found to be present on the principal neurones or their dendrites in these ganglia, despite strong 5-hydroxydopamine labelling of small dense-cored vesicles within cell bodies and dendrites. After acute denervation extremely few residual synapses were found in the ganglion, in areas remote from small granule-containing cells, and these residual synapses were of the cholinergic type. Acute denervation led to the appearance of vacated or isolated postsynaptic densities; such densities were also found, but were fewer in number, in chronically denervated and axotomizeddenervated ganglia. Chronic denervation was associated with the appearance of new synapses, in the proven absence of regeneration of the preganglionic nerve fibres, amounting overall to 12% of the control incidence of synapses per nucleated neuronal profile. The majority of these synapses arose from nerve endings containing a variable population of small dense-cored vesicles which became specifically labelled by 5-hydroxydopamine, indicating that they were of the adrenergic type. The numerical incidence of these synapses showed a significant correlation with the post-operative survival interval. When chronic denervation was combined with post-ganglionic axotomy, the incidence of synapses per nucleated neuronal profile was 32.6% of the control incidence of synapses. The incidence of synapses from nerve terminals containing small dense-cored vesicles in these ganglia was increased three-fold when compared with that in the chronically denervated ganglia. In comparison with acutely denervated ganglia, both chronically denervated and axotomized-denervated ganglia showed also a statistically significant increase of synapses from nerve terminals containing regular clear vesicles but there was no significant difference in the incidence of these synapses between the two long-term experimental groups. Possible post-operative origins of the two classes of synaptic terminals, the one containing small dense-cored vesicles and the other, regular clear vesicles, are discussed. The most likely source of both is considered to be nerve sprouts arising from the intraganglionic portions of the post-ganglionic axons, of adrenergic and cholinergic neurones, respectively. The possible sources of stimuli for sprouting in the denervated and axotomized-denervated ganglia are discussed. Several sources are likely, including the products of neuronal and nerve degeneration and “sprouting factors” arising from the ganglionic neurones, their satellite cells and, or, their targets; these might interact with or be superimposed upon intrinsic changes in the metabolic machinery of the denervated, or axotomized-denervated, neurones. The source of postsynaptic sites for the novel adrenergic synapses is also discussed.