Abstract Background Mass azithromycin distribution reduces child mortality in some settings, potentially through reductions in nasopharyngeal carriage of Streptococcus pneumoniae, but has been associated with increased antimicrobial resistance. Individual-level data are lacking on the impact of azithromycin on antimicrobial resistance over time. Methods We analyzed data from a double-blind, randomized placebo-controlled trial (ClinicalTrials.gov; NCT02414399) which followed 1398 hospitalized Kenyan children to evaluate the impact of a 5-day course of oral azithromycin at discharge from hospital on pneumococcal carriage and the proportion of isolates (among a random sample) resistant to azithromycin. Randomization to azithromycin or placebo (1:1) was stratified by enrollment county (Kisii or Homa Bay). Using generalized estimating equations, we calculated prevalence ratios (PRs) and 95% CIs for the intervention, adjusting for enrollment site. Results Overall, 1253/1398 (89.6%) enrolled children received antibiotics during their hospitalization. Pneumococcal carriage at discharge was similar among children randomized to the azithromycin group (158/702 [22.5%]) compared with the placebo group (171/696 [24.6%]; P = .4) and did not differ at month 3 (65.6% versus 67.0%; PR: 0.98 [0.90, 1.06]) or month 6 (66.7% versus 66.5%; PR: 1.00 [0.92, 1.08]). At discharge, 15.7% of isolates were resistant to azithromycin and there was no difference between azithromycin-treated and placebo groups at month 3 (35/266 [13.2%] versus 32/256 [12.5%]; PR: 1.06 [0.86, 1.66]) or month 6 (41/245 [16.7%] versus 43/243 [17.6%]; PR: 1.01 [0.69, 1.49]). Conclusions Azithromycin treatment did not effect pneumococcal carriage or antimicrobial resistance 3- or 6-months post-randomization. High inpatient antibiotic use in this recently discharged population may have reduced any further impact of azithromycin.