PURPOSE. To explore the sympathetic innervation pattern and the role of sympathetic nervous system control of protein secretion in the exorbital lacrimal glands of normal mice. METHODS. Mouse lacrimal glands were processed for single- and double-label indirect immunofluorescence studies to show their innervation patterns. The sucrose-potassium phosphate-glyoxylic acid method was also used to visualize the adrenergic innervation. The effects of adrenergic and cholinergic agonists on protein secretion were evaluated. RESULTS. The mouse lacrimal gland can be divided into two different areas based on the innervation density and distribution pattern. One area, approximately 10% to 30% of the gland, exhibited much higher innervation density, both parasympathetic and sympathetic, than the rest of the gland. The adrenergic agonists norepinephrine and phenylephrine induced increases in protein secretion that were of a magnitude similar to the increases induced by the cholinergic agonist carbachol at 10-6 to 10-4 M. Isoproterenol, the β-adrenergic agonist, also elicited protein secretion at 10-5 to 10-4 M. CONCLUSIONS. The data indicate that there is extensive sympathetic innervation of the mouse lacrimal gland and that sympathetic input can modulate protein secretion. The division of the lacrimal gland into two areas suggests that the mouse lacrimal gland is a mixed gland and that these two areas may play different roles in secreting tears of different compositions in various situations. These data appear to support the notion that differential secretion is accomplished by activating different populations of secretory cells that are differentially innervated.