Communication is a key component of palliative and end-of-life care. Little is known about comfort with palliative and end-of-life communication among nurses working in rural and urban settings. We assessed this comparison using the 28-item (including 2 ranked items) Comfort with Communication in Palliative and End-of-Life Care instrument. Descriptive analyses of the sample (N = 252) identified statistically significant results differences for age and experience; rural nurses were older and more experienced. Urban nurses reported less comfort than did rural nurses based on composite score analysis (P = .03) and reported less comfort than did rural nurses in talking with patients and families about “end-of-life decisions” (P < .05). Overall, years of experience were significant for more comfort with end-of-life communication. Our instrument could be used within academic settings to establish baseline awareness of comfort with palliative and end-of-life communication and in institutional settings to provide a continuing education bridge from prelicensure through licensure. Moreover, experienced nurses are integral in mentoring new graduates in initiating and sustaining difficult conversations.