In many nerve cells and axons there are specialized appositions (subsurface cisterns) between the surface membrane and endoplasmic reticulum (ER) that closely resemble appositions between the sarcoplasmic reticulum (SR) and surface membrane of muscle (triads, diads). Their presence suggests that the function of the ER of neurons may be similar to the function of the SR of muscle. The squid axon, when loaded with calcium by physiological means and prepared for electron microscopy by rapid freezing and freeze-substitution, contains electron-opaque deposits in the ER as well as in mitochondria. These deposits contain Ca as identified by electron probe X-ray microanalysis. Lightly loaded axons contain smaller amounts of deposits. The ER of axons not specifically loaded with Ca contain small amounts of electron-opaque material while the mitochondria generally do not. Ca-containing deposits were found in the ER and certain other organelles of neurons of Aplysia and ganglion cells and neurites of rat sympathetic ganglia in culture when they were prepared by a modified fixation procedure. Thus, the ER of neurons probably is a Ca-sequestering compartment. Some indirect evidence suggests that Ca may be released from intracellular stores in response to surface membrane stimuli.