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OBJECTIVES A proportion of HIV-infected children with advanced disease develop severe malnutrition soon after antiretroviral therapy (ART) initiation. We tested the hypothesis that systemic inflammation underlies the pathogenesis of severe malnutrition in HIV-infected children. DESIGN Cross-sectional laboratory sub-study in 613 HIV-infected children initiating ART in Uganda and Zimbabwe. METHODS We measured C-reactive protein (CRP), TNFα, IL-6 and soluble CD14 by enzyme-linked immunosorbent assay in cryopreserved plasma at baseline (pre-ART) and week-4 (children with severe malnutrition only). Independent associations between baseline biomarkers and subsequent hospitalization for severe malnutrition were identified using multivariable fractional polynomial logistic regression. RESULTS Compared to children without severe malnutrition (n = 574, median age 6.3 years, median baseline weight-for-age Z-score -2.2), children hospitalized for severe malnutrition post-ART (n = 39, median age 2.3 years, median baseline weight-for-age Z-score -4.8) had higher baseline CRP (median 13.5 (IQR 5.5, 41.1) versus 4.1 (1.4, 14.4) mg/L; p = 0.003) and IL-6 (median 9.2 (6.7, 15.6) versus 5.9 (4.6, 9.3) pg/mL; p < 0.0001), but similar overall TNFα, sCD14 and HIV viral load (all p > 0.06). In a multivariable model, higher pre-ART IL-6, lower TNFα and lower weight-for-age were independently associated with subsequent hospitalization for severe malnutrition. Between weeks 0-4, there was a significant rise in CRP, IL-6 and sCD14, and fall in TNFα and HIV viral load in children hospitalized for severe malnutrition (all p < 0.02). CONCLUSIONS Pre-ART IL-6 and TNFα were more strongly associated with hospitalization for severe malnutrition than CD4 count or viral load, highlighting the importance of inflammation at the time of ART initiation in HIV-infected children.