Inflammatory sinonasal disease is a common problem in patients infected with the human immunodeficiency virus (HIV). Although some patients present with acute or chronic sinusitis, many describe persistent nasal congestion and thick, tenacious postnasal drainage, even in the absence of infection. The efficacy of guaifenesin as a mucolytic is poorly documented and support for its use in this setting is primarily anecdotal. This double-blind, placebo-controlled study assessed changes in nasal symptoms among 23 HIV-infected patients receiving either 3 weeks of guaifenesin (2400 mg daily) or placebo. The guaifenesin group reported less nasal congestion and thinner postnasal drainage compared to the placebo group and these differences were statistically significant (P < .05). Guaifenesin appears to be effective in managing HIV-infected patients with symptomatic rhinosinusitis and may be a useful adjunct for treating acute and chronic sinusitis in this population.