In the United States, antibiotic treatment of acute otitis media is almost mandatory, whereas several other western countries are more reticent. Most clinical trails on antibiotic effect have important methodologic flaws, making an overall interpretation quite difficult. This study determined the effect of penicillin V administration on the secretory capacity of rat middle ear mucosa, during and after acute pneumococcal otitis media, by quantitative studies of the goblet cell density. The right middle ear bullae of 25 rats were inoculated with type 3 pneumococci. Beginning 2 days after inoculation, penicillin V 100 mg/kg/day was administered orally for 5 days. After inoculation, five randomly selected rats were killed on days 4, 8, 16, 90, and 180. The middle ear bullae were removed, split in half, stained with periodic acid-Schiff (PAS)-alcian blue, and the mucosae dissected from the bone. Whole mounts were prepared and the goblet cell density determined in 24 well-defined localities, making a total of 160 counts per ear and covering the entire bulla mucosa. Goblet cell densities were compared with those of 25 normal ears and 25 inoculated, untreated ears. Except on day 4, the penicillin V-treated ears had a significantly lower goblet cell density in almost all localities, on all days of death, when compared with untreated ears. Six months after the acute incident, the goblet cell density was almost normal. However, the enlargement of the mucosal area containing goblet cells seen in untreated ears was unaffected by penicillin V administration. We conclude that administration of penicillin V reduces the increase in secretory capacity of rat middle ear mucosa during and 6 months after acute pneumococcal otitis media.