The initiation of antituberculosis treatment in patients with severe tuberculosis may be accompanied by clinical deterioration and even death before any improvement occurs. To investigate this phenomenon, newly diagnosed human immunodeficiency virus-negative adults with severe tuberculosis were followed for the first 42 days of standard short-course therapy. Clinical status, serum lactate, plasma cytokine, and plasma cytokine receptor levels were monitored on days 0, 3, and 7 and then weekly for up to 42 days. Following 7 days of antituberculosis therapy, a significant transient decrease in mean Karnofsky score (P < .001), a concomitant increase in serum lactate (P = .06), a decrease in patient weight (P = .02), and an increase in plasma tumor necrosis factor-α (TNF-α) concentrations (P = .04) were observed. Plasma levels of soluble interleukin-2 receptor, interferon-γ, interleukin-6, and TNF-α receptor decreased over the 42-day study period. These observations suggest that increases in plasma TNF-α levels may be associated with clinical deterioration observed early in the treatment of severe tuberculosis.