Background The occurrence of nerve ingrowth and its relation to chronic tendon pain (tendinopathy) are still largely unknown. In healthy tendons, the innervation is confined to the paratenon, whereas the tendon proper is devoid of nerve fibers. In this study on the pathogenesis of tendinopathy, the authors examined sensory and sympathetic nerve fiber occurrence in the patellar tendon. Hypothesis Nerve ingrowth and altered expression of sensory and sympathetic neuromediators play a major role in the pathophysiology of pain in patellar tendinopathy. Study Design Case control study; Level of evidence, 3. Methods Biopsies from the patellar tendon in patients with patellar tendinopathy (n = 10) were compared with biopsies from a control group (n = 10) without any previous or current knee symptoms compatible with patellar tendinopathy. The biopsies were stained immunohistochemically for sensory and autonomic nerve markers. The biopsies from the 2 groups were compared using subjective and semiquantitative methods. Results Chronic painful patellar tendons exhibited increased occurrence of sprouting nonvascular sensory, substance P–positive nerve fibers and a decreased occurrence of vascular sympathetic nerve fibers, positive to tyroxin hydroxylase, a marker for noradrenaline. Conclusion The altered sensory-sympathetic innervation suggests a role in the pathophysiology of tendinopathy. Ingrowth of sprouting substance P fibers presumably reflects a nociceptive and maybe a proliferative role, possibly as reactions to repeated microtraumata, whereas the decreased occurrence of tyroxin hydroxylase may represent a reduced antinociceptive role. These findings could be used to develop targeted pharmacotherapy for the specific treatment of tendinopathy.