Background Tanzania has met only 50.1% of the 90% target for diagnosing HIV in children. Context-specific strategies are necessary to find the hidden children for HIV testing. This study assesses the association between caregiver sex and HIV status of orphans and vulnerable children (OVC). Methods Data originate from the community-based, USAID-funded Kizazi Kipya Project, which works towards increasing OVC’s and their caregivers’ uptake of HIV/AIDS and other social services in Tanzania. Included in this study are 39,578 OVC ages 0–19 years who the project served during January-March 2017 in 18 regions of Tanzania and who voluntarily reported their HIV status. Data analysis involved multi-level logistic regression, with OVC HIV status as the outcome and caregiver’s sex the main independent variable.Results Three-quarters (74.3%) of the OVC included in the study had female caregivers, and their overall HIV prevalence was 7.1%. The prevalence was significantly higher (p<0.001) among OVC with male caregivers (7.8%) than among OVC with female caregivers (6.8%), and indeed, multivariate analysis showed that OVC with male caregivers were significantly 40% more likely to be HIV-positive than those with female caregivers (OR=1.40, 95% CI 1.08–1.83). This effect was the strongest among 0–4 year-olds (OR=4.02, 95% CI 1.61–10.03), declined to 1.72 among 5–9 year-olds (OR=1.72, 95% CI 1.02–2.93), and lost significance for children over age 9 years. This effect was adjusted for OVC sex and nutritional status; caregiver marital status, education level, and HIV status; family’s place of residence, size, wealth quintile, and health insurance ownership; and co-residence of multiple OVC. Conclusion OVC in Tanzania with male caregivers have a 40% higher likelihood of being HIVpositive than those with female caregivers. HIV risk assessment activities should target OVC with male caregivers, as well as OVC who have malnutrition, HIV-positive caregivers, or caregivers who do not disclose their HIV status to community volunteers. Further, younger HIV-positive OVC are more likely to live in rural areas, while older HIV-positive OVC are more likely to live in urban areas. These factors should be integrated in HIV risk assessment algorithms to enhance HIV testing yields and pediatric case-finding in the OVC population in Tanzania.