Background. Persons who inject drugs (PWID) in the groin, legs, and/or feet are at high risk for chronic venous ulcers (CVUs). The plasma C-reactive protein (CRP) level is a marker of systemic inflammation. Objective. This pilot study examined CRP levels in plasma and CVU exudate of PWID. The aims were to (1) compare levels of CRP in plasma and exudate; (2) examine if the CRP level in exudate changed over 4 weeks with wound treatment; and (3) examine the relationship of the exudate CRP level with CVU area, CVU age, number of CVUs, and number of comorbidities. Materials and Methods. Persons who inject drugs seeking wound care were enrolled in this Institutional Review Board approved prospective, longitudinal, descriptive study. A blood sample was collected on the first visit (week 1); the plasma was then separated. Wound exudate was collected on swabs during the first visit (week 1) and 4 weeks later (week 4). All samples were stored at -80° C. Samples were eluted from swabs using mass spectrometry grade water then aliquoted for CRP analysis. Results. The participants of the study included 14 PWID (mean age, 62.14 ± 4.52 years; mean number of comorbidities, 5.71 ± 1.90; and mean number of ulcers 2.07 ± 1.07 that were present for a mean of 7.96 ± 11.91 years without healing). C-reactive protein level in plasma was a mean of 6.47 ± 8.56 mg/L, with lower levels found in wound exudate but highly correlated (rho = .925). Exudate CRP levels decreased from week 1 to week 4, and the 2 were highly correlated (rho = .895). Exudate CRP level week 1 was not significantly related to wound area, wound age, number of ulcers, or number of comorbidities. Conclusions. Plasma and exudate CRP levels were highly correlated. Exudate CRP levels decreased across time. Future large-scale wound healing studies should examine CRP levels over a longer duration and as they correlate to wound healing.