AbstractBackgroundAnal squamous cell cancer (ASCC) incidence in Kentucky is increasing at an alarming rate. In 2009, the incidence surpassed the US national average (2.66 vs. 1.77/100,000 people), and currently, Kentucky ranks second by state per capita. The reasons for this rise are unclear. We hypothesize individuals with ASCC in Kentucky have some unique risk factors associated with worse outcomes.MethodsIndividuals with ASCC in a population‐level state database (1995–2016), as well as those treated at two urban university‐affiliated tertiary care centers (2011–2018), were included and analyzed separately. We evaluated patient‐level factors including demographics, tobacco use, stage of disease, HIV‐status, and HPV‐type. We evaluated factors associated with treatment and survival using univariable and multivariable survival analyses.ResultsThere were 1698 individuals in state data and 101 in urban center data. In the urban cohort, 77% of patients were ever‐smokers. Eighty‐four percent of patients had positive HPV testing, and 58% were positive for HPV 16. Seventy‐two percent of patients were positive for p16. Neither smoking, HPV, nor p16 status were associated with disease persistence, recurrence‐free survival, or overall survival (allp> 0.05). Poorly controlled HIV (CD4 count <500) at time of ASCC diagnosis was associated disease persistence (p= 0.032). Stage III disease (adjusted HR = 5.25,p= 0.025) and local excision (relative to chemoradiation; aHR = 0.19,p= 0.017) were significantly associated with reduced recurrence‐free survival.ConclusionsThe rate of ASCC in Kentucky has doubled over the last 10 years, which is outpacing anal SCC rates in the US with the most dramatic rates seen in Kentucky women. The underlying reasons for this are unclear and require further study. There may be other risk factors unique to Kentucky.