BACKGROUND: During acute HIV infection (AHI) HIV actively replicates but seroconversion has not yet occurred. Primary HIV infection (PHI) is characterized by a transient non-specific febrile illness, a massive inflammatory response and the progressive appearance of anti-HIV specific antibodies. In this study we have identified patterns of inflammatory biomarkers associated with the innate immunological reaction prior to completion of a full humoral response. METHODS: A symptom-based screening was used to identify AHI in the Manhica District Hospital in Mozambique. Plasma levels of biomarkers were determined by luminex and ELISA. Anti-HIV antibodies were analysed by flow-cytometry and Western blot. Statistical analyses used Random Forest and logistic regression models. RESULTS: Of 3116 rapid test seronegative or indeterminate individuals, 85 (2.7%) had positive plasma HIV viral load and were enrolled as PHI, of which n=45 (52.9%), n=8 (9.4%), n=12 (14.1%) and n=20 (23.5%) were classified as Fiebig I-III, IV, V and VI stages, respectively by Western-blot. Comparison of individuals at early (Fiebig I-IV) and late (Fiebig V-VI) immune stages identified significant differences in the expression level of plasma BAFF, MCP-1, sCD163 and MIG. This cytokine signature classified patients in the pre-seroconversion phase with a sensitivity of 92.5% and a specificity of 81.2% CONCLUSIONS:: Identification of a cytokine signature specific for the pre-seroconversion stage of PHI may help to understand the earliest HIV pathogenic events and identify new potential targets for immunotherapy aimed at modulating the cytokine response to HIV infection.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.