Background: Case reports suggest that hairy cell leukemia (HCL) may be associated with autoimmune conditions, however no systematic investigations in this area have been undertaken. Methods: Using the United States Surveillance, Epidemiology, and End Results Medicare linked database, we conducted an exploratory study comparing autoimmune conditions in 418 HCL cases (aged 65 years) and 160,086 controls. Results: Overall, the proportion with autoimmune conditions was similar between HCL cases and controls (n = 79 (18.9%) and n = 29,284 (18.3%), respectively). Before diagnosis/selection, there was no overall difference in the prevalence of autoimmune conditions in HCL cases (n = 37, 8.9%) compared with controls (n = 14,085, 8.8%), p = 0.969. However, compared with controls, HCL cases more frequently had sarcoidosis (OR 9.6, 95%CI 2.4-39.5), Sjögren syndrome (OR 6.1, 95%CI 2.0-19.3) and erythema nodosum (OR 37, 95%CI 4.9-284) before diagnosis. Autoimmune conditions were also more common in HCL cases than controls around the time of diagnosis/selection (p < 0.001) but not subsequently. Conclusions: The findings do not support an overall relationship between autoimmune conditions and HCL, although the association with some autoimmune conditions prior to HCL diagnosis may warrant further investigation. Our findings also suggest that autoimmune conditions in HCL patients may be detected around the time of diagnosis.