Clinical manifestations of HIV disease in Africa are nonspecific and easily confused with other endemic diseases. Several studies have compared the prevalence of HIV-related signs and symptoms in infected versus uninfected populations, but little is known about differences in HIV disease manifestations between African men and women across geographic areas. We conducted a cross-sectional study to define predictors of HIV status and assess their differences by gender and country in two African cohorts: 1351 heterosexual couples recruited from a voluntary HIV counseling and testing center in Lusaka, Zambia, and 1458 women recruited from antenatal and pediatric clinics in Kigali, Rwanda. HIV-positive Zambian men and women differed most with respect to prevalence of wasting syndrome (48.1% vs. 35.5%, p < 0.01). Zambian women were more likely to have a disseminated adenopathy than Rwandan women (33.2% vs. 7.8%, p < 0.01) and had a much higher median erythrocyte sedimentation rate (ESR) than either of the two other groups (78 mm/hr vs. 47 mm/hr,p < 0.01). Multivariable logistic regression modeling showed a history of tuberculosis [odds ratio (OR): 2.8-20.7], adenopathy on examination (OR: 4.0-6.3), and an ESR of >65 mm/far (OM: 3.1-5.9) to be strongly predictive of HIV status in all groups. These screening tools, though highly predictive of HIV infection, were insensitive, as most infected persons were asymptomatic. Given these differences in HIV disease manifestation, screening tools based on signs and symptoms should be adapted accordingly. Additional studies are required to evaluate clinical markers as predictors of HIV disease progression and adjust them according to regional and gender differences.