This study aimed to compare the efficacy and safety of letosteine and ambroxol hydrochloride for the treatment of sputum thickening and expectoration difficulty due to either acute or chronic respiratory diseases. Patients (n = 240) were randomized to receive either letosteine + placebo (50 mg thrice daily, Group A) or ambroxol hydrochloride + placebo (30 mg thrice daily, Group B) orally for 5-14 days. The primary outcomes comprised the total effectiveness rate and the total improvement rate. Secondary outcomes included: post-treatment IgA level changes and post-treatment therapeutic evaluation scoring of clinical symptoms. The full analysis set (FAS) comprised 113 patients in Group A and 116 in Group B. The total effectiveness rates were 95.58% for Group A and 95.69% for Group B. The total improvement rates were 99.12% and 99.14% for Group A and Group B, respectively. There were no significant differences between the two groups for any of the primary or secondary outcomes in either the FAS or the per protocol populations (PPS; all P-values > 0.05). Letosteine and ambroxol hydrochloride provided equivalent efficacy and safety in the treatment of sputum thickening and expectoration difficulty due to either acute or chronic respiratory diseases.