Schoolbag carriage is a common occurrence and has been associated with musculoskeletal discomfort in children. The current study investigated the relationship between schoolbag-related musculoskeletal discomfort and individual, physical and psychosocial risk factors in primary school children in Ireland. A cross-sectional survey and pretest-posttest quasi-experimental design was used. The site and intensity of musculoskeletal discomfort was assessed before and after schoolbag carriage to provide a dose-response assessment of schoolbag-related discomfort for the first time. Objective measurements of the children, schoolbags and other additional items were made, and a researcher assisted questionnaire was completed on arrival at school. A total of 529 children (male 55.8%: female 44.2%) with a mean age of 10.6 years +/- 7.14 months were included. The majority had backpacks (93.8%) and 89.7% (n = 445) carried the backpack over 2 shoulders. The mean schoolbag weight (4.8 +/- 1.47 kgs) represented a mean % body weight (%BW) of 12.6 +/- 4.29%. Only 29.9% carried schoolbags that were <10%BW. A significantly greater proportion of normal weight children carried schoolbags that were >10%BW compared to overweight/obese children (p < 0.001). The mean %BW carried was 18.3 +/- 5.03 for those who had an additional item. The majority (77.5%) carried schoolbags to school for <10 min. The prevalence of baseline musculoskeletal discomfort was high (63.4%). Schoolbag-related discomfort was reported more frequently in the shoulders (27.3%) than in the back (15%). The dose-response assessment indicated that both statistically and meaningfully significant increases in discomfort were observed following schoolbag carriage. Multiple logistic regression models indicated that psychosocial factors and a history of discomfort were predictors of schoolbag-related back discomfort, while gender (being female) and a history of discomfort were predictors of schoolbag-related shoulder discomfort. None of the physical factors (absolute/relative schoolbag weight, carrying an additional item, duration of carriage, method of travel to school) were associated with schoolbag-related discomfort. This study highlights the need to consider the multi-factorial nature of schoolbag-related discomfort in children, and also the need to identify background pain as its presence can inadvertently influence the reporting of 'schoolbag-related' discomfort if it is not accounted for.