BACKGROUND: Human immunodeficiency virus (HIV) and cancer co-morbidity in Botswana is high. We sought to explore the distribution of AIDS defining cancers (ADCs) and non-ADCs (NADCs) among people living with HIV (PLHIV) and without HIV during antiretroviral therapy (ART) expansion. METHODS: We included adults aged ≥18 years reported in Botswana National Cancer Registry between 1990 and 2021. We computed crude, age-standardized incidences (ASIRs) and mortality (ASMRs) rates per 100,000 and standardized incidence ratios (SIRs) and mortality ratios (SMRs) of cancers. We used Bayesian spatial modeling and calculated the relative risk (RR) of cancer. RESULTS: We reported 27,726 cases of cancer. Of these, 13,737 (49.5%) were among PLHIV, 3,505 (12.6%) among those without HIV and 9,609 (34.7%) had died from all-causes. During ART expansion, the ASIRs and ASMRs of all cancers, ADCs and NADCs increased significantly in all districts especially Northeast and Southeast in 2002-2007 & 2008-2012 and in Central district during 2016-2021 period. The SIRs and SMRs declined during the study period in several districts. Most of the districts experienced high RR>1.0 of cancer during period 2016-2021, Compared with those without HIV, PLHIV had higher incidences of ADCs, NADCs and sub-types including cervical and Kaposi sarcoma Conclusions: The overall high cancer risk in several districts, the high burden in more urbanized and populous districts, and increased incidences and all-cause mortality among PLHIV in Botswana, highlight the urgent need for improved access to timely cancer screening, diagnosis, and treatment. IMPACT: Our results will contribute to the National Cancer Control Plan development.