The acute sickness response (ASR) is a stereotyped set of symptoms including fatigue, pain, and disturbed mood, which are present in most acute infections. The immunological mechanisms of the ASR are conserved, with variations in severity determined partly by the pathogen, but also by polymorphisms in host genes. The ASR was characterised in three different serologically-confirmed acute infections in Caucasians (n = 484) across four symptom domains or endophenotypes (termed ‘Fatigue’, ‘Musculoskeletal pain’, ‘Mood disturbance’, and ‘Acute sickness’). Correlations were sought with functional single nucleotide polymorphisms in the NLRP3 inflammasone pathway and severity of the endophenotypes. Individuals with severe Fatigue, Musculoskeletal pain, or Mood endophenotypes were more likely to have prior episodes of significant fatigue (11.4 vs. 3.8%, p = 0.07), pain (14.3 vs. 1.2%, p = 0.001), or Mood disturbance (13 vs 1%, p=0.001), suggesting trait characteristics. The high functioning allele of the rs35829419 SNP in NLRP3 was more common in those with severe Fatigue (OR = 13.3, 95% CI: 1.7–104), particularly in a dominant inheritance pattern (OR = 13.4, 95% CI: 1.8–586.3). In a multivariable analysis assuming dominant inheritance, both rs35829419 and the rs4848306 SNP in Interleukin(IL)-1β, were independently associated with severe Fatigue (OR = 29.6, 95% CI: 2.6–330.9 and OR = 13, 95% CI: 2.7–61.8, respectively). The severity of fatigue in acute infection is influenced by genetic polymorphisms in NLRP3 and IL-1β.