Sympathetic nerves in the spleen undergo an injury and sprouting response with development of adjuvant-induced arthritis (AA), a model of rheumatoid arthritis (RA). The objective of the present study was to determine whether this injury and sprouting response is disease-specific or occurs in a non-specific manner similar to injury and sprouting responses following sympathectomy with specific neurotoxins. Changes in noradrenergic (NA) innervation in spleens from Lewis rats 28 days following adjuvant treatment to induce arthritis and/or local 6-hydroxydopamine (6-OHDA) treatment to destroy NA nerves were examined using immunocytochemistry for tyrosine hydroxylase (TH). We observed significant increases in sympathetic innervation of hilar regions, sites of nerve entry into the spleen, and a striking decline in innervation of splenic regions distant to the hilus in arthritic compared to non-arthritic rats. While increased hilar and decreased distal NA innervation in arthritic rats was strikingly similar to that of non-arthritic 6-OHDA-treated rats, there were differences in splenic compartments innervated by sympathetic nerves between these groups. In 6-OHDA-treated rats, NA nerves re-innervated splenic compartments normally innervated by sympathetic nerves. In arthritic rats, sympathetic nerves returned to normally innervated splenic compartments, but also abundantly innervated red pulp. These findings suggest that splenic sympathetic nerves undergo a disease-associated injury/sprouting response with disease development that alters the normal pattern and distribution of NA innervation. The altered sympathetic innervation pattern is likely to change NA signaling to immune cell targets, which could exert long-term regulatory influences on initiation, maintenance, and resolution of immune responses that impact disease pathology.