The following study presents evidence of complement activation in paracoccidioidomycosis (PCM). Twenty-eight untreated patients were studied from endemic areas of Parana in southern Brazil. The activation of the classical pathway, evaluated by the C4d/C4 ratio, was significantly elevated in the patients compared to the control population (p < 0.005). Six patients were examined prospectively with the C4d/C4 assay during treatment and they showed a decrease in this ratio associated with clinical improvement. The activation of the alternative pathway was determined by rocket immunoelectrophoresis of fragment Ba. These levels were also significantly higher in the patient group in comparison to the controls (p < 0.0005). The prospective study also showed a significant variation in the Ba levels associated with clinical improvement (p < 0.01). Furthermore, the levels of C3, C4, CH50 and anti-Paracoccidioides brasiliensis IgG were determined in all patients. The anti-P. brasiliensis IgG levels showed a weak positive correlation with the C4d/C4 ratio (r[S] = 0.45; p < 0.03). The C3, C4 and CH50 levels did not show significant variations from the normal ranges. Our results suggest the involvement of both complement pathways, classical and alternative, in PCM and their association with disease activity.