Tissue-resident alveolar macrophages are important for lung homeostasis and innate immunity. They originate from fetal monocytes and are maintained in the lung through self-renewal or may arise from recruited circulating monocytes. Disturbance of alveolar macrophage function, their numbers or loss of GM-CSF signaling can all underlie pulmonary alveolar proteinosis (PAP). Here, we report eight patients (aged 8–21 years) from four kindreds and three ancestries suffering from recurrent pneumonia, progressive interstitial fibrosis, and PAP. All patients are deficient for the monocyte-chemoattractant protein-1 (CCL-2) receptor 2 (CCR2). Five patients are homozygous and three are compound heterozygous for private or rare CCR2 variants. The variants are loss-of-function for Ca2 +-release and cell migration upon CCL-2 stimulation, when tested by overexpression in monocytic THP-1 cells. Moreover, CCL-2-dependent migration and Ca2+-release of the patients’ monocytes are abolished, while their plasma CCL-2 levels are elevated. Yet, CCR2-deficient cells respond normally to GM-CSF. In addition, the counts, frequencies, and transcriptomes of blood lymphoid and myeloid subsets are normal. Mice deficient for CCR2 display alveolar septal wall thickening and increased number of alveolar type II cells producing surfactant protein C causing increased lung tissue hysteresis. CCR2-deficient mice are vulnerable to mycobacteria, with impaired attraction of blood monocytes to infected tissues. These findings suggest that human CCR2 is essential for the recruitment of monocytes to both pulmonary alveoli and tissues infected with mycobacteria.