Purpose: C-reactive protein (CRP) and white blood cell (WBC) count are routine blood chemistry parameters in monitoring infection. Little is known about the natural history of their serum levels in conservative and operative spondylodiscitis treatment. Methods: Pre- and postoperative serum levels of CRP and WBC count in 145 patients with spondylodiscitis were retrospectively assessed. One hundred and four patients were treated by debridement, spondylodesis, and an antibiotic regime, 41 only with a brace and antibiotics. The results of the surgical group were compared to 156 patients fused for degenerative disc disease (DDD). Results: Surgery had a significant effect on peak postoperative CRP levels. In surgically managed patients, CRP peaked at 2–3 days after surgery (spondylodiscitis: pre-OP: 90 mg/dl vs. post-OP days 2–3: 146 mg/dl; DDD: 9 mg/dl vs. 141 mg/dl; p < 0.001), followed by a sharp decline. Although values were higher for spondylodiscitis patients, dynamics of CRP values were similar in both groups. Nonoperative treatment showed a slower decline. Surgically managed spondylodiscitis showed a higher success rate in identifying bacteria. Specific antibiotic treatment led to a more predictable decline of CRP values. WBC did not show an interpretable profile. Conclusion: CRP is a predictable serum parameter in patients with spondylodiscitis. WBC count is unspecific. Initial CRP increase after surgery is of little value in monitoring infection. A preoperative CRP value, and control once during the first 3 days after surgery is sufficient. Closer monitoring should then be continued. Should a decline not be observed, therapy needs to be scrutinized, antibiotic treatment reassessed, and concomitant infection contemplated.