Background: Blood transfusion is a known risk factor for transmitting infectious diseases, including the human immunodeficiency virus, due to false negatives and false positives in HIV rapid diagnostic test results. This study determines the percentage of false negatives and positives among prospective blood donors in two major referral hospitals in Kebbi State, Northwest Nigeria. Method: A total of 900 sera were collected from potential blood donors from January to July 2020 in two general hospitals in Kebbi State. All donors were screened for HIV infection using Determine HIV-1/2, Uni-Gold, and STAT-PAK. The presence of viral antigen in the donor serum was tested using the p24 diagnostic technique. Data were analyzed using SPSS version 16. Descriptive statistics were used to determine frequencies and percentages. The chi-square test compared categorical variables. Result: Out of 900 blood donors, 27 (3%) were reactive to determine HIV-1 and HIV-2. One-third (9) of the 27 reactives on Determine HIV 1/2 were non-reactives on Uni-Gold. The nine (1%) non-reactive on Uni-Gold were also non-reactive on STAT-PAK and p24 viral antigens. The 873 (97%) samples that were non-reactive on Determine HIV 1/2, Uni-Gold, and STAT-PAK were non-reactive on HIV p24 antigens. The result showed that one-third of the blood donors who were not positive on determination were false positives, as confirmed on Uni-Gold, STAT-PAK, and the Ultra HIV Ag–Ab p24 antigen ELISA. Conclusion: The results suggest that using a lone rapid technique for HIV diagnosis is not recommended. Hence, a double-blind strategy should reduce HIV endemicity and optimize blood safety.