Chitosan, the deacetylated derivative of chitin, is used as biomaterial in diverse settings. It is also found on pathogens and can be proinflammatory. Shorter derivatives of chitosan can be generated chemically or enzymatically, chitosan oligosaccharides (ChOS). There is variation in the chemical composition of ChOS, including size distribution, but in general, they have been described as inert or anti-inflammatory. Active human chitinases can cleave chitin and chitosan, while inactive chitinases bind both but do not cleave. Both active and inactive chitinases have important roles in the immune response. The inactive chitinase YKL-40 is expressed highly during inflammation and has been proposed as a marker of poor prognosis. YKL-40 acts as a negative regulator of the inflammasome and as a positive regulator of angiogenesis. Levels of YKL-40 can therefore regulate levels of inflammation, the extent of angiogenesis, and the process of inflammation resolution. This study shows that chitosan leads to reduced secretion of YKL-40 by primary human macrophages and that this is concomitant with inflammasome activation. This was most pronounced with a highly deacetylated ChOS. No effect on the secretion of the active chitinase Chit-1 was detected. Smaller and more acetylated ChOS did not affect YKL-40 levels nor inflammasome activation. We conclude that this effect on the levels of YKL-40 is a part of the proinflammatory mechanisms of chitosan and its derivatives.