Background Peripheral artery disease is characterized by an intense inflammatory process that can be associated with a higher mortality rate, particularly in chronic limb‐threatening ischemia (CLTI). This study aims to compare the evolution of inflammatory markers between patients with claudication with those with CLTI at 3, 6, and 12 months. Methods and Results An observational, single‐center, and prospective study was conducted. A total of 119 patients with peripheral artery disease (65 with claudication and 54 with CLTI) were observed and inflammatory markers collected at admission and 3, 6, and 12 months. At admission, patients with CLTI, when compared with patients with claudication, had significantly higher serum levels of C‐reactive protein and fibrinogen (positive acute‐phase proteins) and lower serum level of albumin, total cholesterol, and high‐density lipoprotein (negative acute‐phase proteins): C‐reactive protein (g/dL), 2.90 (25th–75th percentile, 2.90–4.90) versus 6.80 (25th–75th percentile, 2.90–53.26) ( P =0.000); fibrinogen (mg/dL), 293.00 (25th–75th percentile, 269.25–349.00) versus 415.50 (25th–75th percentile, 312.00–615.75) ( P =0.000); total cholesterol (mg/dL), 161.79±95% [152.74–170.85] versus 146.42%±95% [135.30–157.53] ( P =0.034); high‐density lipoprotein (mg/dL), 50.00 (25th–75th percentile, 41.00–60.00) versus 37.00 (25th–75th percentile, 30.00–45.50) ( P =0.000); albumin (g/dL): 4.00 (25th–75th percentile, 3.70–4.20) versus 3.60 (25th–75th percentile, 3.10–4.00) ( P =0.003). The association between CLTI and total cholesterol was lost after adjusting for confounders. Three months after the resolution of the CLTI, there was an increase in the levels of negative acute‐phase proteins and a decrease in positive acute‐phase proteins. These inflammatory proteins did not register an evolution in patients with claudication. The differences in the inflammatory proteins between groups disappeared at 6 months. Conclusions CLTI has an inflammatory environment that can be partially reverted after resolution of the ischemic process, emphasizing the importance of timely intervention.