Background The bacterium Rhodococcus equi can cause severe pneumonia in foals. The absence of a licensed vaccine and limited effectiveness of commercial R. equi hyperimmune plasma (RE‐HIP) create a great need for improved prevention of this disease. Hypothesis Plasma hyperimmune to the capsular polysaccharide poly‐ N ‐acetyl glucosamine (PNAG) would be significantly more effective than RE‐HIP at mediating complement deposition and opsonophagocytic killing (OPK) of R. equi . Animals Venipuncture was performed on 9 Quarter Horses. Methods The ability of the following plasma sources to mediate complement component 1 (C1) deposition onto either PNAG or R. equi was determined by ELISA: (1) PNAG hyperimmune plasma (PNAG‐HIP), (2) RE‐HIP, and (3) standard non‐hyperimmune commercial plasma (SP). For OPK, each plasma type was combined with R. equi , equine complement, and neutrophils isolated from horses (n = 9); after 4 hours, the number of R. equi in each well was determined by quantitative culture. Data were analyzed using linear mixed‐effects regression with significance set at P < .05. Results The PNAG‐HIP and RE‐HIP were able to deposit significantly ( P < .05) more complement onto their respective targets than the other plasmas. The mean proportional survival of R. equi opsonized with PNAG‐HIP was significantly ( P < .05) less (14.7%) than that for SP (51.1%) or RE‐HIP (42.2%). Conclusions and Clinical Importance Plasma hyperimmune to PNAG is superior to RE‐HIP for opsonizing and killing R. equi in vitro. Comparison of these 2 plasmas in field trials is warranted because of the reported incomplete effectiveness of RE‐HIP.