Necrotizing fasciitis (NF) is a rare mono-/polymicrobial skin infection that spreads to underlying tissues. NF is quickly progressing and leads to life threatening situations. Immediate surgical debridement together with i.v. antibiotic administration is required to avoid fatal outcome. Early diagnosis is often delayed due to underestimation or confusion with cellulitis. We now compared the initial clinical and laboratory presentation of NF and cellulitis in detail to assess if a typical pattern can be identified that aids timely diagnosis of NF and avoidance of fatal outcome. 138 different clinical and laboratory features of 29 NF patients were compared to those of 59 age- and gender matched patients with severe erysipelas requiring a subsequent hospitalization time of ≥10 days. Differences in clinical presentation were not obvious; however, NF patients suffered significantly more often from strong pain. NF patients exhibited dramatically elevated CRP levels (5-fold, p>0.001). The overall laboratory risk indicator for necrotizing fasciitis (LRINEC) score was significantly higher in NF patients as compared to cellulitis. However, a modification of the score (alteration of laboratory parameters, addition of clinical parameters) led to a clear improvement of the score with a higher positive predictive value without losing specificity. In summary, clinical differentiation of NF from cellulitis appears to be hard. ‘Pain out of proportion’ may be an early sign for NF. An improvement of the LRINEC score emphasizing only relevant laboratory and clinical findings as suggested may aid the early diagnosis of NF in the future leading to improvement of disease outcome by enabling rapid adequate therapy.