A new topical fixed-dose combination product containing clindamycin (1%, formulated as 1.2% clindamycin phosphate, CLNP 1.2%) with low strength (3%) benzoyl peroxide (BPO) in a methylparaben-free gel vehicle (CLNP 1.2%–BPO 3%-MPF) has been developed for the treatment of acne. The objective of this study was to determine the relative bioavailability of clindamycin and clindamycin sulfoxide from CLNP 1.2%–BPO 3%-MPF compared with clindamycin phosphate 1.2%-BPO 5% in a methylparaben-preserved gel vehicle (CLNP 1.2%–BPO 5%-MP) and clindamycin phosphate 1.2%–BPO 5% in a methylparaben-free gel vehicle (CLNP 1.2%–BPO 5%-MPF), and to determine whether exposure is affected by BPO concentration (3% vs. 5%) when applied topically. Seventy-two subjects with moderate–severe acne were randomized to receive CLNP 1.2%-BPO 3%-MPF, CLNP 1.2%–BPO 5%-MP, or CLNP 1.2%–BPO 5%-MPF in a 5-day, open-label, and parallel-group study. Cmax and AUC values for clindamycin were highest for CLNP 1.2%–BPO 5%-MP, followed by CLNP 1.2%–BPO 3%-MPF and CLNP 1.2%–BPO 5%-MPF, but differences were not statistically significant. Systemic exposure to clindamycin and clindamycin sulfoxide was low and comparable between the formulations. Results indicate that differences in BPO concentration do not influence clindamycin bioavailability.