Ozonation was effective in degrading six sulfonamides: sulfaquinoxaline, sulfamethazine, sulfamethoxazole, sulfathiazole, sulfadimethoxine, and sulfadiazine (C0 = 100 μg L−1). The degradation experiments were based on two variables: pH (3.0, 7.0 and 11.0) and aqueous matrix (ultrapure water, tap water, and surface water). In all matrices studied and pH 11.0, more than 99% of the drugs were degraded with the highest applied ozone dose (65 mg L−1), when compared with other pH values. Also, comparing the three aqueous matrices, the ultrapure water was the one that required the lowest ozone dosage (6.4 mg L−1) to reach the same degradation efficiency of the sulfonamides. Caffeine is known as an environment contamination indicator. Therefore, this does not intend to totally remove this compound, but to verify its degradation level compared with the sulfonamides.