Purpose: This study aimed to estimate the association between the number of teeth and general quality of life in adults. Methods: A population-based study was conducted with 1720 individuals aged 20–59 years residing in Florianópolis, Brazil, in 2009. Data were collected at participants’ households using a structured questionnaire. In 2012, a second wave was undertaken with 1222 individuals. Oral examinations were performed for number of teeth, prevalence of functional dentition (≥21 natural teeth), and shortened dental arch (SDA), which were considered the main exposures. General quality of life was the outcome and was assessed with the WHO Abbreviated Instrument for Quality of Life (WHOQOL-BREF). Covariates included sociodemographic factors, health-related behaviors, and chronic diseases. Multivariable linear regression models were performed to test the associations between the main exposures and the outcome adjusted for covariates. Results: In 2012, 1222 individuals participated in the study (response rate = 71.1%). Having more teeth was associated with greater scores on physical domain of the WHOQOL-BREF [β = 0.24 (95% CI 0.01; 0.46)] after adjustment for covariates. Absence of functional dentition was associated with lower scores on the physical domain [β = −3.94 (95% CI −7.40; −0.48)] in the adjusted analysis. There was no association between both SDA definitions and the domains of general quality of life. Conclusions: Oral health as measured by tooth loss was associated with negative impacts on general quality of life assessed by the WHOQOL-BREF. There was a lack of evidence that SDA is a condition that negatively affects general quality of life.