We reviewed mortality data among medical inpatients at a tertiary hospital in Botswana to identify risk factors for adverse inpatient outcomes. This review was a prospective analysis of inpatient admissions. All medical admissions to male and female medical wards were recorded over a six-month period between 1 November 2011 and 30 April 2012. Data collected included patient demographics, HIV status (positive, negative, unknown), HIV testing history, HIV related treatment and serological history, admission and discharge diagnoses, and mortality status at final discharge or transfer. Of 972 patients admitted during the surveillance period, 427 (43.9%) were known to be HIV-positive on admission, 144 (14.8%) were known to be HIV-negative, and 401 (41.3%) had an unknown HIV status. Of those with unknown status, 131 (32.7%) were tested for HIV during admission and among these 35 (27.5%) were HIV-positive. Including patients with known mortality status following transfer, 172 (17.9%) patients died during the hospitalization. Death occurred in 105 (23%) of known HIV-positive patients, compared with 31 (13%) of known HIV-negative patients (p = 0.002, HR = 1.56 in adjusted analyses). Among HIV-positive patients who died, a low CD4 cell count (<200 cells/mm3) was associated with death. Overall, patients who died had significantly more neurological and respiratory-related presenting complaints than patients who survived. In conclusion, we identified higher overall mortality among HIV-positive patients at a tertiary hospital in Botswana, and low rates of in-hospital HIV testing and antiretroviral therapy initiation. These data demonstrate that despite available antiretroviral therapy in the population for over a decade, HIV continues to add excess burden to the hospital system and adds to inpatient mortality in Botswana.